BIOELECTRICAL PHENOMENA IN NERVE CELLS

BIOELECTRICAL PHENOMENA IN NERVE CELLS. PHYSIOLOGY OF SYNAPSES. PHYSIOLOGY OF INTERNEURONAL CONNECTIONS.

 

The goal of physiology is to explain the physical and chemical factors that are responsible for the origin, development, and progression of life. Each type of life, from the very simple virus to the largest tree or to the complicated human being, has its own functional characteristics. Therefore, the vast field of physiology can be divided into viral physiology, bacterial physiology, cellular physiology, plant physiology, human physiology, and many more subdivisions.

 

EXCERPT FROM INSTRUCTION OF FIRE SAFETY MEASURES IN THE CASE OF BUILDING EXPLUATATION IN TERNOPIL STATE MEDICAL ACADEMY NAMED BY I. Ya. GORBACHEVSKY

 

General safety rules at laboratory use

 

1. Students are obligated to dress a doctor’s smock before entering the laboretory room.

2. Every student are obligated to work at constantly fixed by him (her) place. Matching another work place is strictly forbidden without instructors’ permission.

3. Students are forbidden to work at the laboratory in instructor or laboratory assistant absence.

4. Students are categorically forbidden to make experimental jobs irrelevant to education process execution.

5. Students are permitted to set at each work only being instructed in protection of labor and fire safety, after instructors’ permission. Instruction fixes in periodical briefing journal.

6. Tytors, laborators and students are obligated to know the fire danger of the labs lodgment, liquids and materials used in, also stick to fire safety rules.

7. All jobs concerned with isolation of noxious substances fire-explode-dangerous vapors and gases have to be hold at functional draft hoods only. Draft hoods have to be made of incombustible materials. The use of out of order draft hoods is strictly forbidden.

8. FORBIDDEN to leave work place out of observation, alighted burners and other heating supplies.

9. Collaborators and students are obligated to know the location of fire-extinguishing means and be able to use them practically in case of fire origin.

10. In labs lodgment FORBIDDEN:

 – to obstruct the passages, and also passages leading to fire-extinguishing means, to create passages between the equipment less then 1meter.

 – to leave tarred pieces of cloth and paper at work place.

 – to keep in work lodgments any kind of substances with unknown fire dangerous properties.

 

CELLS AS THE LIVING UNITS OF THE BODY

 

The basic living unit of the body is the cell, and each organ is an aggregate of many different ceils held together by intercellular supporting structures. Each type of cell is specially adapted to perform one or a few particular functions. For instance, the red blood ceils, 25 trillion in each human being, transport oxygen from the lungs to the tissues. Although this type of cell is perhaps the most abundant in the body, there are about another 75 trillion cell. The entire body, then, contains about 100 trillion ceils. Although the many cells of the body often differ markedly from each other, all of them have certain basic characteristics that are alike. For instance, in all ceils, oxygen combines with breakdown products of carbohydrate, fat, or protein to release the energy required for cell function. Furthermore, the general chemical mechanisms for changing nutrients into energy are basically the same in all cells, and all the cells also deliver the end products of their chemical reactions into the surrounding fluids.

 

The Body: an Open System with an Internal Environment

The existence of unicellular organisms is the epitome of life in its simplest form. Even simple protists must meet two basic but essentially conflicting demands in order to survive. A unicellular organism must, on the one hand, isolate itself from the seeming disorder of its inanimate surroundings, yet, as an “open system”, it is dependent on its environment for the exchange of heat, oxygen, nutrients, waste materials, and information. “Isolation” is mainly ensured by the cell membrane, the hydrophobic properties of which prevent the potentially fatal mixing of hydrophilic components in watery solutions inside and outside the cell. Protein molecules within the cell membrane ensure the permeability of the membrane barrier. They may exist in the form of pores (channels) or as more complex transport proteins known as carriers. Both types are selective for certain substances, and their activity is usually regulated. The cell membrane is relativelywell permeable to hydrophobic molecules such as gases. This is useful for the exchange of O2 and CO2 and for the uptake of lipophilic signal substances, yet exposes the cell to poisonous gases such as carbon monoxide (CO) and lipophilic noxae such as organic solvents. The cell membrane also contains other proteins—namely, receptors and enzymes. Receptors receive signals from the external environment and convey the information to the interior of the cell (signal transduction), and enzymes enable the cell to metabolize extracellular substrates. Let us imagine the primordial sea as the external environment of the unicellular organism. This milieu remains more or less constant, although the organism absorbs nutrients from it and excretes waste into it. In spite of its simple structure, the unicellular organism is capable of eliciting motor responses to signals from the environment. This is achieved by moving its pseudopodia or flagella, for example, in response to changes in the food concentration.

The evolution from unicellular organisms to multicellular organisms, the transition from specialized cell groups to organs, the emergence of the two sexes, the coexistence of individuals in social groups, and the transition from water to land have tremendously increased the efficiency, survival, radius of action, and independence of living organisms.

This process required the simultaneous development of a complex infrastructure within the organism. Nonetheless, the individual cells of the body still need a milieu like that of the primordial sea for life and survival. Today, the extracellular fluid is responsible for providing constant environmental conditions, but the volume of the fluid is no longer infinite. In fact, it is even smaller than the intracellular volume. Because of their metabolic activity, the cells would quickly deplete the oxygen and nutrient stores within the fluids and flood their surroundings with waste products if organs capable of maintaining a stable internal environment had not developed. This is achieved through homeostasis, a process by which physiologic self-regulatory mechanisms maintain steady states in the body through coordinated physiological activity.

The term homeostasis is used by physiologists to mean maintenance of static or constant conditions in the internal environment. Essentially all of the organs and tissues of the body perform functions that help to maintain these constant conditions. For instance, the lungs provide oxygen to the extracellular fluid to continually replenish the oxygen that is being used by the ceils, the kidneys maintain constant ion concentrations, and the gastrointestinal system provides nutrients. A large segment of this text is concerned with the manner in which each organ or tissue contributes to homeostasis. To begin this discussion, in this chapter, the different functional systems of the body and their contributions to homeostasis are outlined; then we also outline briefly the basic theory of the control systems that cause the functional systems to operate in harmony with one another.

 

Specialized organs ensure the continuous absorption of nutrients, electrolytes and water and the excretion of waste products via the urine and feces. The circulating blood connects the organs to every inch of the body, and the exchange of materials between the blood and the intercellular spaces (interstices) creates a stable environment for the cells. Organs such as the digestive tract and liver absorb nutrients and make them available by processing, metabolizing and distributing them throughout the body.

 

 

The lung is responsible for the exchange of gases (O2 intake, CO2 elimination), the liver and kidney for the excretion of waste and foreign substances, and the skin for the release of heat. The kidney and lungs also play an important role in regulating the internal environment, e.g., water content, osmolality, ion concentrations, pH (kidney, lungs) and O2 and CO2 pressure (lungs). The specialization of cells and organs for specific tasks naturally requires integration, which is achieved by convective transport over long distances (circulation, respiratory tract), humoral transfer of information (hormones), and transmission of electrical signals in the nervous system, to name a few examples.

These mechanisms are responsible for supply and disposal and thereby maintain a stable internal environment, even under conditions of extremely high demand and stress. Moreover, they control and regulate functions that ensure survival in the sense of preservation of the species. Important factors in this process include not only the timely development of reproductive organs and the availability of fertilizable gametes at sexual maturity, but also the control of erection, ejaculation, fertilization, and nidation. Others include the coordination of functions in the mother and fetus during pregnancy and regulation of the birth process and the lactation period.

The central nervous system(CNS) processes signals from peripheral sensors (single sensory cells or sensory organs), activates outwardly directed effectors (e.g., skeletal muscles), and influences the endocrine glands. The CNS is the focus of attention when studying human or animal behavior. It helps us to locate food and water and protects us from heat or cold. The central nervous systemalso plays a role in partner selection, concern for offspring even long after their birth, and integration into social systems. The CNS is also involved in the development, expression, and processing of emotions such as desire, listlessness, curiosity, wishfulness, happiness, anger, wrath, and envy and of traits such as creativeness, inquisitiveness, self-awareness, and responsibility. This goes far beyond the scope of physiology— which in the narrower sense is the study of the functions of the body—and, hence, of this book. Although behavioral science, sociology, and psychology are disciplines that border on physiology, true bridges between them and physiology have been established only in exceptional cases.

 

Nervous System. The nervous system is composed of  three major parts: the sensory input portion, the central  nervous system (or integrative portion), and the motor output portion. Sensory receptors detect the state of the body or the state of the surroundings. For instance, receptors present everywhere in the skin apprise one every time an object touches the skin at any point. The eyes are sensory organs that give one a visual image of the surrounding area. The ears also are sensory organs.

The central nervous system is composed of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and determine reactions that the body performs in response to the sensations. Appropriate signals are then transmitted through the motor output portion of the nervous system to carry out one’s desires. A large segment of the nervous system is called the autonomic system. It operates at a subconscious level and controls many functions of the internal organs, including the level of pumping activity by the heart, movements of the gastrointestinal tract, and glandular secretion.

 

Hormonal System of Regulation. Located in the body are eight major endocrine glands that secrete chemical substances called hormones. Hormones are transported in the extracellular fluid to all parts of the body to help regulate cellular function. For instance, thyroid hormone increases the rates of most chemical reactions in all ceils. In this way, thyroid hormone helps to set the tempo of bodily activity. Insulin controls glucose metabolism; adrenocortical hormones control sodium ion, potassium ion, and protein metabolism: and parathyroid hormone controls bone calcium and phosphate. Thus, the hormones are a system of regulation that complements the nervous system. The nervous system regulates mainly muscular and secretory activities of the body, whereas the hormonal system regulates mainly metabolic functions.

Most control systems of the body act by negative feedback, which can best be explained by reviewing some of the homeostatic control systems mentioned previously. In the regulation of carbon dioxide concentration, a high concentration of carbon dioxide in the extracellular fluid increases pulmonary ventilation. This in turn decreases the extracellular fluid carbon dioxide concentration because the lungs then excrete greater amounts of carbon dioxide from the body. In other words, the high concentration causes a decreased concentration, which is negative to the initiating stimulus. Conversely, if the carbon dioxide concentration falls too low, this causes a feedback increase in the concentration. This response also is negative to the initiating stimulus. In the arterial pressure-regulating mechanisms, a high pressure causes a series of reactions that promote a lowered pressure, or a low pressure causes a series of reactions that promote an elevated pressure. In both instances, these effects are negative with respect to the initiating stimulus.

Therefore, in general, if some factor becomes excessive or deficient, a control system initiates negative feedback, which consists of a series of changes that return the factor toward a certain mean value, thus maintaining homeostasis.

 

Control and Regulation. In order to have useful cooperation between the specialized organs of the body, their functions must be adjusted to meet specific needs. In other words, the organs must be subject to control and regulation. Control implies that a controlled variable such as the blood pressure is subject to selective external modification, for example, through alteration of the heart rate. Because many other factors also affect the blood pressure and heart rate, the controlled variable can only be kept constant by continuously measuring the current blood pressure, comparing it with the reference signal (set point), and continuously correcting any deviations. If the blood pressure drops—due, for example, to rapidly standing up from a recumbent position—the heart rate will increase until the blood pressure has been reasonably adjusted. Once the blood pressure has risen above a certain limit, the heart rate will decrease again and the blood pressure will normalize. This type of closed-loop control is called a negative feedback control system or a control circuit. It consists of a controller with a programmed set-point value (target value) and control elements (effectors) that can adjust the controlled variable to the set point.

The system also includes sensors that continuously measure the actual value of the controlled variable of interest and report it (feedback) to the controller, which compares the actual value of the controlled variable with the set-point value and makes the necessary adjustments if disturbance-related discrepancies have occurred. The control system operates either fromwithin the organ itself (autoregulation) or via a superordinate organ such as the central nervous system or hormone glands.

Unlike simple control, the elements of a control circuit can work rather imprecisely without causing a deviation from the set point (at least on average). Moreover, control circuits are capable of responding to unexpected dis turbances.

 

 

In the case of blood pressure regulation, for example, the system can respond to events such as orthostasis or sudden blood loss. The type of control circuits described above keep the controlled variables constant when disturbance variables cause the controlled variable to deviate from the set point. Within the body, the set point is rarely invariable, but can be “shifted” when requirements of higher priority make such a change necessary. In this case, it is the variation of the set point that creates the discrepancy between the nominal and actual values, thus leading to the activation of regulatory elements.

Since the regulatory process is then triggered by variation of the set point (and not by disturbance variables), this is called servocontrol or servomechanism. Fever and the adjustment of muscle length by muscle spindles and motor neurons are examples of servocontrol. In addition to relatively simple variables such as blood pressure, cellular pH, muscle length, body weight and the plasma glucose concentration, the body also regulates complex sequences of events such as fertilization, pregnancy, growth and organ differentiation, as well as sensory stimulus processing and the motor activity of skeletal muscles, e.g., to maintain equilibrium while running. The regulatory process may take parts of a second (e.g., purposeful movement) to several years (e.g., the growth process).

In the control circuits described above, the controlled variables are kept constant on average, with variably large, wave-like deviations. The sudden emergence of a disturbance variable causes larger deviations that quickly normalize in a stable control circuit (!E, test subject no. 1). The degree of deviation may be slight in some cases but substantial in others. The latter is true, for example, for the blood glucose concentration, which nearly doubles after meals. This type of regulation obviously functions only to prevent extreme rises and falls (e.g., hyper- or hypoglycemia) or chronic deviation of the controlled variable. More precise maintenance of the controlled variable requires a higher level of regulatory sensitivity (high amplification factor). However, this extends the settling time and can lead to regulatory instability, i.e., a situation where the actual value oscillates back and forth between extremes.

Oscillation of a controlled variable in response to a disturbance variable can be attenuated by either of two mechanisms. First, sensors with differential characteristics ensure that the intensity of the sensor signal increases in proportion with the rate of deviation of the controlled variable from the set point. Second, feedforward control ensures that information regarding the expected intensity of disturbance is reported to the controller before the value of the controlled variable has changed at all.

Feedforward control can be explained by example of physiologic thermoregulation, a process in which cold receptors on the skin trigger counterregulation before a change in the controlled value (core temperature of the body) has actuallyoccurred. The disadvantage of having only D sensors in the control circuit can be demonstrated by example of arterial pressosensors (pressoreceptors) in acute blood pressure regulation. Very slow but steady changes, as observed in the development of arterial hypertension, then escape regulation. In fact, a rapid drop in the blood pressure of a hypertensive patient will even cause a counterregulatory increase in blood pressure. Therefore, other control systems are needed to ensure proper long-term blood pressure regulation.

 

 

The Cell. The cell is the smallest functional unit of a living organism. In other words, a cell (and no smaller unit) is able to perform essential vital functions such as metabolism, growth, movement, reproduction, and hereditary transmission. Growth, reproduction, and hereditary transmission can be achieved by cell division.

All cells consist of a cell membrane, cytosol or cytoplasm (ca. 50 vol.%), and membrane-bound subcellular structures known as organelles. The organelles of eukaryotic cells are highly specialized. For instance, the genetic material of the cell is concentrated in the cell nucleus, whereas “digestive” enzymes are located in the lysosomes. Oxidative ATP production takes place in the mitochondria.

The cell nucleus contains a liquid known as karyolymph, a nucleolus, and chromatin. Chromatin contains deoxyribonucleic acids (DNA), the carriers of genetic information. Two strands of DNA forming a double helix (up to 7cm in length) are twisted and folded to form chromosomes 10 μm in length. Humans normally have 46 chromosomes, consisting of 22 autosomal pairs and the chromosomes that determine the sex (XX in females, XY in males). DNA is made up of a strand of three-part molecules called nucleotides, each of which consists of a pentose (deoxyribose) molecule, a phosphate group, and a base. Each sugar molecule of the monotonic sugar–phosphate backbone of the strands (. . .deoxyribose – phosphate–deoxyribose. . .) is attached to one of four different bases. The sequence of bases represents the genetic code for each of the roughly 100 000 different proteins that a cell produces during its lifetime (gene expression). In a DNA double helix, each base in one strand of DNA is bonded to its complementary base in the other strand according to the rule: adenine (A) with thymine (T) and guanine (G) with cytosine (C).

 

The nuclear envelope consists of two membranes (two phospholipid bilayers) tha tmerge at the nuclear pores. The two membranes consist of different materials. The external membrane is continuous with the membrane of the endoplasmic reticulum.

 

Transport In, Through and Between Cells. The lipophilic cell membrane protects the cell interior from the extracellular fluid, which has a completely different composition. This is imperative for the creation and maintenance of a cell’s internal environment by means of metabolic energy expenditure. Channels (pores), carriers, ion pumps and the process of cytosis allow transmembrane transport of selected substances. This includes the import and export of metabolic substrates and metabolites and the selective transport of ions used to create or modify the cell potential, which plays an essential role in excitability of nerve and muscle cells. In addition, the effects of substances that readily penetrate the cell membrane in most cases (e.g.,water and CO2) can be mitigated by selectively transporting certain other substances.

 

 

This allows the cell to compensate for undesirable changes in the cell volume or pH of the cell interior. Intracellular Transport The cell interior is divided into different compartments by the organelle membranes. In some cases, very broad intracellular spaces must be crossed during transport. For this purpose, a variety of specific intracellular transport mechanisms exist, for example: Nuclear pores in the nuclear envelope provide the channels for RNA export out of the nucleus and protein import into it; Protein transport from the rough endoplasmic reticulum to the Golgi complex; Axonal transport in the nerve fibers, in which distances of up to 1meter can be crossed. These transport processes mainly take place along the filaments of the cytoskeleton. Example: while expending ATP, the microtubules set dynein-bound vesicles in motion in the one direction, and kinesinbound vesicles in the other.

Intracellular Transmembrane Transport Main sites:

Lysosomes: Uptake of H+ ions from the cytosol and release of metabolites such as amino acids into the cytosol; ! Endoplasmic reticulum (ER): In addition to a translocator protein (!p. 10), the ER has two other proteins that transport Ca2+. Ca2+

can be pumped from the cytosol into the ER by a Ca2+-ATPase called SERCA (sarcoplasmic endoplasmic reticulum Ca2+-transporting ATPase). The resulting Ca2+ stores can be released into the cytosol via a Ca2+ channel (ryanodine receptor, RyR) in response to a triggering signal.

Mitochondria: The outer membrane contains large pores called porins that render it permeable to small molecules (5 kDa), and the inner membrane has high concentrations of specific carriers and enzymes. Enzyme complexes of the respiratory chain transfer electrons from high to low energy levels, thereby pumping H+ ions from the matrix space into the intermembrane space, resulting in the formation of an H+ ion gradient directed into the matrix. This not only drives ATP synthetase (ATP production), but also promotes the inflow of pyruvate – and anorganic phosphate (symport). Ca2+ ions that regulate Ca2+-sensitive mitochondrial enzymes in muscle tissue can be pumped into the matrix space with ATP expenditure, thereby allowing the mitochondria to form a sort of Ca2+ buffer space for protection against dangerously high concentrations of Ca2+ in the cytosol. The insidenegative membrane potential (caused by H+ release) drives the uptake of ADP3 – in exchange for ATP4 – (potential-driven transport). Transport between Adjacent Cells In the body, transport between adjacent cells occurs either via diffusion through the extracellular space (e.g., paracrine hormone effects) or through channel-like connecting structures (connexons) located within a so-called gap junction or nexus (!C). A connexon is a hemichannel formed by six connexin molecules. One connexon docks with another connexon on an adjacent cell, thereby forming a common channel through which substances with molecular masses of up to around 1 kDa can pass. Since this applies not only for ions such as Ca2+, but also for a number of organic substances such as ATP, these types of cells are united to form a close electrical and metabolic unit (syncytium), as is present in the epithelium, many smooth muscles (singleunit type), the myocardium, and the glia of the central nervous system.

 

 

Electric coupling permits the transfer of excitation, e.g., from excited muscle cells to their adjacent cells, making it possible to trigger awave of excitation across wide regions of an organ, such as the stomach, intestine, biliary tract, uterus, ureter, atrium, and ventricles of the heart. Certain neurons of the retina and CNS also communicate in this manner (electric synapses). Gap junctions in the glia and epithelia help to distribute the stresses that occur in the course of transport and barrier activities (see below) throughout the entire cell community. However, the connexons close when the concentration of Ca2+ (in an extreme case, due to a hole in cell membrane) or H+ concentration increases too rapidly. In other words, the individual (defective) cell is left to deal with its own problems wheecessary to preserve the functionality of the cell community.

Transport through Cell Layers Multicellular organisms have cell layers that are responsible for separating the “interior” from the “exterior” of the organism and its larger compartments. The epithelia of skin and gastrointestinal, urogenital and respiratory tracts, the endothelia of blood vessels, and neuroglia are examples of this type of extensive barrier. They separate the immediate extracellular space from other spaces that are greatly different in composition, e.g., those filled with air (skin, bronchial epithelia), gastrointestinal contents, urine or bile (tubules, urinary bladder, gallbladder), aqueous humor of the eye, blood (endothelia) and cerebrospinal fluid (blood–cerebrospinal fluid barrier), and from the extracellular space of the CNS (blood–brain barrier). Nonetheless, certain substances must be able to pass through these cell layers. This requires selective transcellular transport with import into the cell followed by export from the cell. Unlike cells with a completely uniform plasma membrane (e.g., blood cells), epi- and endothelial cells are polar cells, as defined by their structure and transport function. Hence, the apical membrane (facing exterior) of an epithelial cell has a different set of transport proteins from the basolateral membrane (facing the blood). Tight junctions (described below) at which the outer phospholipid layer of the membrane folds over, prevent lateral mixing of the two membranes.

Whereas the apical and basolateral membranes permit transcellular transport, paracellular transport takes place between cells. Certain epithelia (e.g., in the small intestinal and proximal renal tubules) are relatively permeable to small molecules (leaky), whereas others are less leaky (e.g., distal nephron, colon). The degree of permeability depends on the strength of the tight junctions (zonulae “ occludentes) holding the cells together. The paracellular pathway and the extent of its permeability (sometimes cation-specific) are essential functional elements of the various epithelia. Macromolecules can cross the barrier formed by the endothelium of the vessel wall by transcytosis, yet paracellular transport also plays an essential role, especially in the fenestrated endothelium. Anionic macromolecules like albumin, which must remain in the bloodstream because of its colloid osmotic action, are held back by the wall charges at the intercellular spaces and, in some cases, at the fenestra.

Long-distance transport between the various organs of the body and between the body and the outside world is also necessary. Convection is the most important transport mechanism involved in long-distance transport.

Passive Transport by Means of Diffusion. Diffusion is movement of a substance owing to the random thermal motion (brownian movement) of its molecules or ions (!A1) in all directions throughout a solvent. Net diffusion or selective transport can occur only when the solute concentration at the starting point is higher than at the target site. (Note: unidirectional fluxes also occur in absence of a concentration gradient—i.e., at equilibrium— but net diffusion is zero because there is equal flux in both directions.) The driving force of diffusion is, therefore, a concentration gradient. Hence, diffusion equalizes concentration differences and requires a driving force: passive transport (= downhill transport). Example: When a layer of O2 gas is placed onwater, the O2 quickly diffuses into thewater along the initially high gas pressure gradient. As a result, the partial pressure of O2 (Po2) rises, and O2 can diffuse further  downward into the next O2-poor layer ofwater (!A1). (Note: with gases, partial pressure is used in lieu of concentration.) However, the steepness of the Po2 profile or gradient (dPo2/ dx) decreases (exponentially) in each subsequent layer situated at distance x from the O2 source. Therefore, diffusion is only feasible for transport across short distances within the body. Diffusion in liquids is slower than in gases. The diffusion rate is the amount of substance that diffuses per unit of time. It is proportional to the area available for diffusion (A) and the absolute temperature (T) and is inversely proportional to the viscosity of the solvent and the radius (r) of the diffused particles.

Since the driving “force”—i.e., the concentration gradient (dC/dx)—decreases with distance, as was explained above, the time required for diffusion increases exponentially with the distance traveled (t#x2). If, for example, a molecule travels the first μm in 0.5 ms, it will require 5 s to travel 100 μmand a whopping 14 h for 1 cm. Returning to the previous example (!A2), if the above-water partial pressure of free O2 diffusion (!A2) is kept constant, the Po2 in the water and overlying gas layer will eventually equalize and net diffusion will cease (diffusion equilibrium). This process takes place within the body, for example, when O2 diffuses from the alveoli of the lungs into the bloodstream and when CO2 diffuses in the opposite direction. Let us imagine two spaces, a and b containing different concentrations (Ca”Cb) of an uncharged solute. The membrane separating the solutions has pores #x in length and with total cross-sectional area of A. Since the pores are permeable to the molecules of the dissolved substance, the molecules will diffuse from a to b, with Ca–Cb = #C representing the concentration gradient. Ifwe consider only the spaces a and b (while ignoring the gradients dC/dx in the pore, as shown in B2, for the sake of simplicity), When diffusion occurs through the lipid membrane of a cell, one must consider that hydrophilic substances in the membrane are sparingly soluble (compare intramembrane gradient in C1 to C2) and, accordingly, have a hard time penetrating the membrane by means of “simple” diffusion. The oil-and-water partition coefficient (k) is a measure of the lipid solubility of a substance.

 

 

Osmosis, Filtration and Convection Water flow or volume flow (JV) across a membrane, in living organisms is achieved through osmosis (diffusion of water) or filtration. They can occur only if the membrane is water-permeable. This allows osmotic and hydrostatic pressure differences (!” and !P) across the membrane to drive the fluids through it.

 

 

Active Transport. Active transport occurs in many parts of the body when solutes are transported against their concentration gradient (uphill transport) and/or, in the case of ions, against an electrical potential. All in all, active transport occurs against the electrochemical gradient or potential of the solute. Since passive transport mechanisms represent “downhill” transport, they are not appropriate for this task. Active transport requires the expenditure of energy. A large portion of chemical energy provided by foodstuffs is utilized for active transport once it has been made readily available in the form of ATP. The energy created by ATP hydrolysis is used to drive the transmembrane transport of numerous ions, metabolites, and waste products. According to the laws of thermodynamics, the energy expended in these reactions produces order in cells and organelles—a prerequisite for survival and normal function of cells and, therefore, for the whole organism. In primary active transport, the energy produced by hydrolysis of ATP goes directly into ion transport through an ion pump. This type of ion pump is called an ATPase. They establish the electrochemical gradients rather slowly, e.g., at a rate of around 1 μmol s–1 m–2 of membrane surface area in the case of Na+-K+- ATPase. The gradient can be exploited to achieve rapid ionic currents in the opposite direction after the permeability of ion channels has been increased. Na+ can, for example, be driven into a nerve cell at a rate of up to 1000 μmol s–1 m–2 during an action potential. ATPases occur ubiquitously in cell membranes (Na+-K+-ATPase) and in the endoplasmic reticulum and plasma membrane (Ca2+-ATPase), renal collecting duct and stomach glands (H+,K+ -ATPase), and in lysosomes (H+-ATPase). They transport Na+, K+, Ca2+ and H+, respectively, by primarily active mechanisms. All except H+-ATPase consist of 2 !-subunits and 2 “-subunits (P-type ATPases). The !-subunits are phosphorylated and form the ion transport channel. Na+-K+-ATPase is responsible for maintenance of intracellular Na+ and K+ homeostasis and, thus, for maintenance of the cell membrane potential. During each transport cycle (!A1, A2), 3 Na+ and 2 K+ are “pumped” out of and into the cell, respectively, while 1 ATP molecule is used to phosphorylate the carrier protein (!A2b). Phosphorylation first changes the conformation of the protein and subsequently alters the affinities of the Na+ and K+ binding sites. The conformational change is the actual ion transport step since it moves the binding sites to the opposite side of the membrane. Dephosphorylation restores the pump to its original state (!A2e–f). The Na+/K+ pumping rate increases when the cytosolic Na+ concentration rises— due, for instance, to increased Na+ influx, or when the extracellular K+ rises. Therefore, Na+,K+-activatable ATPase is the full name of the pump.Na-+K+-ATPase is inhibited by ouabain and cardiac glycosides. Secondary active transport occurs when uphill transport of a compound (e.g., glucose) via a carrier protein (e.g., sodium glucose transporter type 2, SGLT2) is coupled with the passive (downhill) transport of an ion (in this example Na+; !B1). In this case, the electrochemical Na+ gradient into the cell (created by Na+-K+-ATPase at another site on the cell membrane; provides the driving force needed for secondary active uptake of glucose into the cell. Coupling of the transport of two compounds across a membrane is called cotransport, which may be in the form of symport or antiport. Symport occurs when the two compounds (i.e., compound and driving ion) are transported across the membrane in the same direction. Antiport (countertransport) occurs when they are transported in opposite directions. Antiport occurs, for example, when an electrochemical Na+ gradient drives H+ in the opposite direction by secondary active transport. The resultingH+ gradient can then be exploited for tertiary active symport of molecules such as peptides. Electroneutral transport occurs when the net electrical charge remains balanced during transport, e.g., during Na+/H+ antiportand Na+-Cl– symport. Small charge separation occurs in electrogenic (rheogenic) transport, e.g., in Na+-glucose0 symport (!B1), Na+-amino acid0 symport, 2Na+-amino acid– symport, or H+-peptide symport.

 

 

The chemical Na+ gradient provides the sole driving force for electroneutral transport (e.g., Na+/H+ antiport), whereas the negative membrane potential provides an additional driving force for electrogenication–coupled cotransport into the cell. When secondary active transport (e.g., of glucose) is coupled with the influx of not one but two Na+ ions (e.g., SGLT1 symporter), the driving force is doubled. The aid of ATPases is necessary, however, if the required “uphill” concentration ratio is several decimal powers large, e.g., 106 in the extreme case ofH+ ions across the luminalmembrane of parietal cells in the stomach. ATPase-mediated transport can also be electrogenic or electroneutral, e.g., Na+-K+-ATPase (3 Na+/2 K+; cf. p. 46) or H+/K+-ATPase (1H+/1 K+), respectively. Characteristics of active transport: It can be saturated, i.e., it has a limited maximum capacity (Jmax). ! It is more or less specific, i.e., a carrier molecule will transport only certain chemically similar substances which inhibit the transport of each other (competitive inhibition).

Variable quantities of the similar substances are transported at a given concentration, i.e., each has a different affinity (~1/KM) to the transport system. Active transport is inhibited when the energy supply to the cell is disrupted. All of these characteristics except the last apply to passive carriers, that is, to uniportermediated (facilitated) diffusion. Cytosis is a completely different type of active transport involving the formation of membrane-bound vesicles with a diameter of 50–400 nm. Vesicles are either pinched off from the plasma membrane (exocytosis) or incorporated into it by invagination (endocytosis) in conjunction with the expenditure of ATP. In cytosis, the uptake and release of macromolecules such as proteins, lipoproteins, polynucleotides, and polysaccharides into and out of a cell occurs by specific mechanisms similar to those involved in intracellular transport.  Endocytosis can be broken down into different types, including pinocytosis, receptor-mediated endocytosis, and phagocytosis. Pinocytosis is characterized by the continuous unspecific uptake of extracellular fluid and molecules dissolved in it through relatively small vesicles. Receptor-mediated endocytosis involves the selective uptake of specific macromolecules with the aid of receptors. This usually begins at small depressions (pits) on the plasma membrane surface. Since the insides of the pits are often densely covered with the protein clathrin, they are called clathrin-coated pits. The receptors involved are integral cell membrane proteins such as those for low-density lipoprotein (LPL; e.g., in hepatocytes) or intrinsic factor-bound cobalamin (e.g., in ileal epithelial cells). Thousands of the same receptor type or of different receptors can converge at coated pits, yielding a tremendous increase in the efficacy of ligand uptake. The endocytosed vesicles are initially coated with clathrin, which is later released.

The vesicles then transform into early endosomes, and most of the associated receptors circulate back to the cell membrane. The endocytosed ligand is either exocytosed on the opposite side of the cell (transcytosis, see below), or is digested by lysosomes. Phagocytosis involves the endocytosis of particulate matter, such as microorganisms or cell debris, by phagocytes in conjunction with lysosomes. Small digestion products, such as amino acids, sugars and nucleotides, are transported out of the lysosomes into the cytosol, where they can be used for cellular metabolism or secreted into the extracellular fluid. When certain hormones such as insulin bind to receptors on the surface of target cells, hormonereceptor complexes can also enter the coated pits and are endocytosed (internalized) and digested by lysosomes. This reduces the density of receptors available for hormone bind ing.

 

 

In other words, an increased hormone supply down-regulates the receptor density. Exocytosis is a method for selective export of macromolecules out of the cell (e.g., pancreatic enzymes) and for release of many hormones (e.g., posterior pituitary hormone) or neurotransmitters. These substances are kept “packed” and readily available in (clathrin-coated) secretory vesicles, waiting to be released when a certain signal is received (increase in cytosolic Ca2+). The “packing material” (vesicle membrane) is later re-endocytosed and recycled. Exocytotic membrane fusion also helps to insert vesicle-bound proteins into the plasma membrane.The liquid contents of the vesicle then are automatically emptied in a process called constitutive exocytosis. In constitutive exocytosis, the protein complex coatomer (coat assembly protomer) takes on the role of clathrin (see above). Within the Golgi membrane, GNRP (guanine nucleotide-releasing protein) phosphorylates the GDP of the ADP-ribosylation factor (ARF) to GTP ), resulting in the dispatch of vesicles from the trans-Golgi network. ARF-GTP complexes then anchor on the membrane and bind with coatomer (!D2), thereby producing coatomer-coated vesicles. The membranes of the vesicles contain v-SNAREs (vesicle synaptosome-associated protein receptors), which recognize t-SNAREs (target-SNAREs) in the target membrane (the plasma membrane, in this case). This results in cleavage of ARF-GTP, dissociation of ARF-GDP and coatomer molecules and, ultimately, to membrane fusion and exocytosis (!D4, D5) to the extracellular space (ECS).

Transcytosis is the uptake of macromolecules such as proteins and hormones by endocytosis on one side of the cell, and their release on the opposite side. This is useful for transcellular transport of the macromolecules across cell layers such as endothelia.

Cell Migration. Most cells in the body are theoretically able to move from one place to another or migrate, but only a fewcell species actually do so. The sperm are probably the only cells with a special propulsion mechanism. By waving their whip-like tail, the sperm can travel at speeds of up to around 2000 μm/min. Other cells also migrate, but at much slower rates. Fibroblasts, for example,move at a rate of around 1.2 μm/min. When an injury occurs, fibroblasts migrate to the wound and aid in the formation of scar tissue. Cell migration also plays a role in embryonal development. Chemotactically attracted neutrophil granulocytes and macrophages can even migrate through vessel walls to attack invading bacteria. Cells of some tumors can also migrate to various tissues of the body or metastasize, thereby spreading their harmful effects. Cells migrate by “crawling” on a stable surface. The following activities occur during cell migration:

Back end of the cell: (a) Depolymerization of actin and tubulin in the cytoskeleton; (b) endocytosis of parts of the cell membrane, which are then propelled forward as endocytotic vesicles to the front of the cell, and (c) release of ions and fluids from the cell.

Front end of the cell (lamellipodia): (a) Polymerization of actin monomers is achieved with the aid of profilin. The monomers are propelled forward with the help of plasma membrane-based myosin I (fueled by ATP); (b) reinsertion of the vesicles in the cell membrane; (c) uptake of ions and fluids from the environment.

Parts of the cell membrane that are not involved in cytosis are conveyed from front to back, as on a track chain. Since the cell membrane is attached to the stable surface (primarily fibronectin of the extracellular matrix in the case of fibroblasts), the cell moves forward relative to the surface. This is achieved with the aid of specific receptors, such as fibronectin receptors in the case of fibroblasts. Electrical Membrane Potentials and

Ion Channels. An electrical potential difference occurs due to the net movement of charge during ion transport. A diffusion potential develops for instance, when ions (e.g., K+) diffuse (down a chemical gradient) out of a cell, making the cell interior negative relative to the outside. The rising diffusion potential then drives the ions back into the cell (potentialdriven ion transport). Outward K+ diffusion persists until equilibrium is reached. At equilibrium, the two opposing forces become equal and opposite. In other words, the sum of the two or the electrochemical gradient (and thereby the electrochemical potential) equals zero, and there is no further net movement of ions (equilibrium concentration) at a certain voltage (equilibrium potential).

At equilibrium potential, the chemical gradient will drive just as many ions of species X in the one direction as the electrical potential does in the opposite direction. The electrochemicalpotential (Em– Ex) or so-called electrochemical driving “force”, will equal zero, and the sum of ionic inflow and outflow or the net flux (Ix) will also equal zero. Membrane conductance (gx), a concentration- dependent variable, is generally used to describe the permeability of a cell membrane to a given ion instead of the permeability coefficient P (see Eq. 1.5 on p. 22 for conversion).

Realistic values in resting nerve cells are: fK = 0.90, fNa = 0.03, fCl = 0.07; EK = – 90mV, ENa =+ 70mV, ECl = – 83mV. Inserting these values into equation 1.21 results in an Em of – 85mV. Thus, the driving forces (= electrochemical potentials = Em–Ex), equal + 5mV for K+, – 145mV for Na+, and – 2mV for Cl–. The driving force for K+ efflux is therefore low, though

gK is high.

 

 

Despite a high driving force for Na+, Na+ influx is lowbecause the gNa and fNa of resting cells are relatively small. Nonetheless, the sodium current, INa, can rise tremendously when large numbers of Na+ channels open during an action potential.

Electrodiffusion. The potential produced by the transport of one ion species can also drive other cations or anions through the cell membrane, provided it is permeable to them. The K+diffusion potential leads to the efflux of Cl–, for example, which continues until ECl = Em. According to Equation 1.18, this means that the cytosolic Cl– concentration is reduced to 1/25 th of the extracellular concentration (passive distribution of Cl– between cytosol and extracellular fluid). In the above example, therewas a small electrochemical Cl– potentialdriving Cl– out of the cell (Em – ECl = – 2 mV). This means that the cytosolic Cl– concentration is higher than in passive Cl– distribution (ECl = Em). Therefore, Cl– ions must have been actively taken up by the cell, e.g., by a Na+- Cl– symport carrier: active distribution of Cl– . To achieve ion transport, membranes have a variable number of channels (pores) specific for different ion species (Na+, Ca2+, K+, Cl–, etc.). The conductance of the cell membrane is therefore determined by the type and number of ion channels that are momentarily open. Patch–clamp techniques permit the direct measurement of ionic currents through single ion channels. Patch–clamp studies have shown that the conductance of a membrane does not depend on the change of the pore diameter of its ion channels, but on their average frequency of opening. The ion permeability of a membrane is therefore related to the open-probability of the channels in question. Ion channels open in frequent bursts.

Several ten thousands of ions pass through the channel during each individual burst, which lasts for only a few milliseconds. During a patch–clamp recording, the opening (0.3–3 μm in diameter) of a glass electrode is placed over a cell membrane in such a way that the opening covers only a small part of the membrane (patch) containing only one or a small number of ion channels. The whole cell can either be left intact, or a membrane patch can excised for isolated study. In singlechannel recording, the membrane potential is kept at a preset value (voltage clamp). This permits the measurement of ionic current in a single channel. The measurements are plotted as current (I) over voltage (V). The slope of the I/V curve corresponds to the conductance of the channel for the respective ion species. The zero-current potential is defined as the voltage at which the I/V curve intercepts the x-axis of the curve (I = 0). The ion species producing current I can be deducedfrom the zero-current potential. In example B, the zero-current potential equals – 90mV. Under the conditions of this experiment, an electrochemical gradient exists only for Na+ and K+, but not for Cl– (!B). At these gradients, EK = – 90mVand ENa = + 90mV. As EK equals the zero-current potential, the channel is exclusively permeable to K+ and does not allow other ions like Na+ to pass. The channel type can also be determined by adding specific channel blockers to the system. Control of ion channels (!C). Channel open-probability is controlled by five main factors:

Membrane potential, especially in Na+, Ca2+ and K+ channels ierve and muscle fibers.

External ligands that bind with the channel. This includes acetylcholine on the postsynaptic membrane of nicotinic synapses (cation channels), glutamate (cation channels), and glycine or GABA (Cl– channels).

Intracellular messenger substances such as: — cAMP (e.g., in Ca2+ channels in myocardial cells and Cl– channels in epithelial cells); — cGMP (plays a role in muscarinergic effects of acetylcholine and in excitation of the retinal rods); — IP3 (opening of Ca2+ channels of intracellular Ca2+ stores); — Small G-proteins (Ca2+ channels of the cell membrane); — Tyrosine kinases (Cl– and K+ channels during apoptosis); — Ca2+ (affects K+ channels and degree of activation of rapid Na+ channels).

 

 

Role of Ca2+ in Cell Regulation The cytosolic Ca2+ concentration, [Ca2+]i, (ca. 0.1 to 0.01 μmol/L) is several decimal powers lower than the extracellular Ca2+ concentration [Ca2+]o (ca. 1.3 mmol/L). This is because Ca2+ is continuously pumped from the cytosol into intracellular Ca2+ stores such as the endoplasmic and sarcoplasmic reticulum (! p. 17 A), vesicles, mitochondria and nuclei or is transported out of the cell. Both processes occur by primary active transport (Ca2+-ATPases) and, in the case of efflux, by additional secondary active transport through Ca2+/3Na+ antiporters.

A rise in [Ca2+]i is a signal for many important cell functions, including myocyte contraction, exocytosis of neurotransmitters in presynaptic nerve endings, endocrine and exocrine hormone secretion, the excitation of certain sensory cells, the closure of gap junctions in various cells, the opening of other types of ion channels, and the migration of leukocytes and tumor cells as well as thrombocyte activation and sperm mobilization.Some of these activities are mediated by calmodulin. A calmodulin molecule can bind up to 4 Ca2+ ions when the [Ca2+]i rises. The Ca2+-calmodulin complexes activate a number of different enzymes, including calmodulin-dependent protein kinase II (CaMkinase II) and myosin light chain kinase (MLCK), which is involved in smooth muscle contraction. [Ca2+]i oscillation is characterized by multiple brief and regular [Ca2+]i increases (Ca2+ spikes) in response to certain stimuli or hormones (!B). The frequency, not amplitude, of[Ca2+]i oscillation is the quantitative signal for cell response. When low-frequency [Ca2+]i oscillation occurs, CaM-kinase II, for example, is activated and phosphorylates only its target proteins, but is quickly and completely deactivated. High-frequency [Ca2+]i oscillation results in an increasing degree of autophosphorylation and progressively delays thedeactivation of the enzyme. As a result, the activity of the enzyme decays more andmore slowly between [Ca2+]i signals, and each additional [Ca2+]i signal leads to a summation of enzyme activity. As with action potentials, this frequency-borne, digital all-or-none type of signal transmission provides a much clearer message than the [Ca2+]i amplitude, which is influenced by a number of factors. Ca2+ sensors. The extracellular Ca2+ concentration [Ca2+]o plays an important role in blood coagulation and bone formation as well as in nerve and muscle excitation. [Ca2+]o is tightly controlled by hormones such as PTH, calcitriol and calcitonin, and represents the feedback signal in this control circuit. The involved Ca2+sensors are membrane proteins that detect high [Ca2+]o levels on the cell surface and dispatch IP3 and DAG (diacylglycerol) as intracellular second messengers with the aid of a Gq protein. IP3 triggers an increase in the [Ca2+]i of parafollicular C cells of the thyroid gland. This induces the exocytosis of calcitonin, a substance that reduces [Ca2+]o. In parathyroid cells, on the other hand, a high [Ca2+]o reduces the secretion of PTH, a hormone that increases the [Ca2+]o. This activity is mediated by DAG and PKC (protein kinase C) and, perhaps, by a (Gi protein-mediated) reduction in the cAMP concentration. Ca2+ sensors are also located on osteoclasts as well as on renal and intestinal epithelial cells.

The protein channels are believed to provide watery pathways through the interstices of the protein molecules. In fact, computerized three-dimensional reconstructions of some of these proteins have demonstrated actual curving tube-shaped channels from the extracellular to the intracellular ends. Therefore, substances can diffuse by simple diffusion directly through these channels from one side of the membrane to the other. The protein channels are distinguished by two important characteristics: (1) they are often selectively permeable to certain substances and (2) many of the channels can be opened or closed by gates.

 

Selective Permeability of Many Protein Channels. Many of the protein channels are highly selective for the transport of one or more specific ions or molecules. This results from the characteristics of the channel itself, such as its diameter, its shape, and the nature of the electrical charges along its inside surfaces. To give an example, one of the most important of the protein channels, the so-called sodium channels, calculates to be only 0.3 by 0.5 nanometer in size, but more important, the inner surfaces of these channels are strongly negatively charged. These strong negative charges pull small dehydrated sodium ions into these channels, actually pulling the sodium ions away from their hydrating water molecules. Once in the channel, the sodium ions then diffuse in either direction according to the usual laws of diffusion. Thus, the sodium channel is specifically selective for the passage of sodium ions. Conversely, another set of protein channels is selective for potassium transport. These channels calculate to be slightly smaller than the sodium channels, only 0.3 by 0.3 nanometer, but they are not negatively charged. Therefore, no strong attractive force is pulling ions into the channels, and the ions are not pulled away from the water molecules that hydrate them. The hydrated form of the potassium ion is considerably smaller than the hydrated form of sodium because the sodium ion attracts far more water molecules than does the potassium. Therefore, the smaller hydrated potassium ions can pass easily through this small channel, whereas sodium ions are mainly rejected, thus once again providing selective permeability for a specific ion.

Gating of Protein Channels. Gating of protein channels provides a means for controlling ion permeability of the channels. This is shown in both the upper and the lower panels of Figure 4-4 for selective gating of sodium and potassium ions. It is believed that the gates are actual gatelike extensions of the transport protein molecule, which can close over the opening of the channel or can be lifted away from the opening by a conformational change in the shape of the protein molecule itself. In the case of the sodium channels, this gate opens and closes at the end of the channel on the outside of the cell membrane, whereas for the potassium channels, it opens and closes at the intracellular end of the channel.

The opening and closing of gates are controlled in two principal ways:

1. Voltage gating. In this instance, the molecular conformation of the gate responds to the electrical potential across the cell membrane. For instance, there is a strong negative charge on the inside of the cell membrane, and this causes the outside sodium gates to remain tightly closed: conversely, when the inside of the membrane

loses its negative charge, these gates open suddenly and allow tremendous quantities of sodium to pass inward through the sodium pores. This is the basic cause of action potentials ierves that are responsible for nerve signals. These gates are on the intracellular ends of the potassium channels, and they open when the inside of the cell membrane becomes positively charged. The opening of these gates is partly responsible for terminating the action potential.

2. Chemical gating (“ligand” gating). Some protein channel gates are opened by the binding of a chemical substance (a “ligand”) with the protein; this causes a conformational change in the protein molecule that opens or closes the gate. This is called chemical gating or ligand gating. One of the most important instances of chemical gating is the effect of acetylcholine on the so-called acetylcholine channel. This opens the gate of this channel, providing a negatively charged pore about 0.65 nanometer in diameter that allows all uncharged molecules and positive ions smaller than this diameter to pass through. This gate is exceedingly important for the transmission of nerve signals from one nerve cell to another and from nerve cells to muscle cells to cause muscle contraction.

 

Open-State, Closed-State of Gated Channels. The gate of the channel snaps open and then snaps closed, each open state lasting only a fraction of a millisecond up to several milliseconds. This demonstrates the rapidity with which conformational changes can occur during the opening and closing of the protein molecular gates. At one voltage potential, the channel may remain closed all the time or almost all the time, whereas at another voltage level it may remain open either all or most of the time. At in-between voltages, as shown in the figure, the gates tend to snap open and closed intermittently, giving an average current flow somewhere between the minimum and the maximum.

 

Patch-Clamp Method for Recording Ion Current Flow Through Single Channels. One might wonder how it is technically possible to record ion current flow through single protein channels. This has been achieved by using the “‘patch-clamp” method. Very simply, a micropipette, having a tip diameter of only 1 or 2 micrometers, is abutted against the outside of a cell membrane. Then suction is applied inside the pipette to pull the membrane slightly into the tip of the pipette. This creates a seal where the edges of the pipette touch the cell membrane. The result is a minute membrane “patch” at the tip of the pipette through which electrical current flow can be recorded. Alternatively, the small cell membrane patch at the end of the pipette can be torn away from the cell. The pipette with its sealed patch is then inserted into a free solution. This allows the concentra- tions of the ions both inside the micropipette and in the out- side solution to be altered as desired. Also, the voltage be- tween the two sides of the membrane can be set at will–that is, “clamped” to a given voltage. It has been possible to make such patches small enough that one often finds only a single channel protein in the mem- brane patch that is being studied. By varying the concentra- tions of different ions as well as the voltage across the mem- brane, one can determine the transport characteristics of the single channel and also its gating properties.

 

Basic physics of membrane potentials. The potassium concentration is great

inside the membrane, whereas that outside the membrane is very low. Let us assume that the membrane in this instance is permeable to the potassium ions but not to any other ions. Because of the large potassium concentration gradient from the inside toward the outside, there is a strong tendency for extra numbers of potassium ions to diffuse outward. As they do so, they carry positive charges to the outside, thus creating a state of electropositivity outside the membrane but electronegativity on the inside because of negative anions that remain behind and do not diffuse outward along with the potassium. Within a millisecond or so, the potential becomes great enough to block further net potassium diffusion to the exterior despite the high potassium ion concentration gradient. In the normal large mammaliaerve fiber, the potential difference required is about 94 millivolts, with negativity inside the fiber membrane. These ions are also positively charged, and this time the membrane is highly permeable to the sodium ions but impermeable to all other ions. Diffusion of the positively charged sodium ions to the inside creates a membrane potential now of opposite polarity,with negativity outside and positivity inside. Again, the membrane potential rises high enough within milliseconds to block further net diffusion of sodium ions to the inside; however, this time, in the large mammaliaerve fiber, the potential is about 61 millivolts positivity inside the fiber.

Thus, we see that a concentration difference of ions across a selectively permeable membrane can, under appropriate conditions, create a membrane potential. In later sections of this chapter, we will see that many of the rapid changes in membrane potentials observed during nerve and muscle impulse transmission result from the occurrence of such rapidly changing diffusion potentials.

 

Relation of the Diffusion Potential to the Concentration Difference–the Nernst Equation. The potential level across the membrane that exactly opposes net diffusion of a particular ion through the membrane is called the Nernst potential for that ion, a term. The magnitude of this Nernst potential is determined by the ratio of the concentrations of that specific ion on the two sides of the membrane. The greater this ratio, the greater the tendency for the ion to diffuge in one direction, and therefore the greater the Nernst potential required to prevent the diffusion. The following equation, called the Nernst equation, can be used to calculate the Nernst potential for any univalent ion at normal body temperature of 98.6°F (37°C):

Thus, when the concentration of positive potassium ions on the inside is 10 times that on the outside, the log of 10 is 1, so that the Nernst potential c’,dculates to be -61 millivolts inside the membrane.

 

Measuring the Membrane Potential. The method for measuring the membrane potential is simple in theory but often difficult in practice because of the small sizes of most of the fibers. Figure 5-2 shows a small filled pipette containing an electrolyte solution that is impaled through the cell membrane to the interior of the fiber. Then another electrode, called the “indifferent electrode,” is placed in the extracellular fluid, and the potential difference between the inside and outside of the fiber is measured using an appropriate voltmeter. This voltmeter is a highly sophisticated electronic apparatus that is capable of measuring very small voltages despite extremely high resistance to electrical flow through the tip of the micropipette, which has a lumen diameter usually less than 1 micrometer and a resistance often as great as I billion ohms. For recording rapid changes in the membrane potential during transmission of nerve impulses, the microelectrode is connected to an oscilloscope, as explained later in the chapter.

The electrical potential that is measured at each point in or near the nerve fiber membrane, beginning at the left side of the figure and passing to the ,right. As long as the electrode is outside the nerve membrane, the potential that is recorded is zero, which is the potential of the extracellular fluid. Then, as the recording electrode passes through the voltage charge area at the cell membrane (called the electrical dipole layer), the potential decreases abruptly to -90 millivolts. Moving across the center of the fiber, the potential remains at a steady -90-millivolt level but reverses back to zero the instant it passes through the membrane on the opposite side of the cell. To create a negative potential inside the membrane, only enough positive ions must be transported outward to develop the electrical dipole layer at the membrane itself. All the remaining ions inside the nerve fiber still can be both positive and negative ions. Therefore, an incredibly small number of ions need to be transferred through the membrane to establish the normal potential of -90 millivolts inside the nerve fiber;. Also, an equally small number of positive ions moving from outside to the inside of the fiber can reverse the potential from -90 millivolts to as much as +35 millivolts within as little as јo,o00 of a second. Rapid shifting of ions in this manner causes the nerve signals that we discuss in subsequent sections of this chapter.

 

Neuron Structure and Function. An excitable cell reacts to stimuli by altering its membrane characteristics. There are two types of excitable cells: nerve cells, which transmit and modify impulses within the nervous system, and muscle cells, which contract either in response to nerve stimuli or autonomously. The humaervous system consists of more than 1010 nerve cells or neurons. The neuron is the structural and functional unit of the nervous system. A typical neuron (motor neuron) consists of the soma or cell body and two types of processes: the axon and dendrites. Apart from the usual intracellular organelles (!p. 8ff.), such as a nucleus and mitochondria, the neuron contains neurofibrils and neurotubules. The neuron receives afferent signals (excitatory and inhibitory) from a few to sometimes several thousands of other neurons via its dendrites (usually arborescent) and sums the signals along the cell membrane of the soma (summation). The axon arises from the axon hillock of the soma and is responsible for the transmission of efferent neural signals to nearby or distant effectors (muscle and glandular cells) and adjacent neurons. Axons often have branches (collaterals) that further divide and terminate in swellings called synaptic knobs or terminal buttons. If the summed value of potentials at the axon hillock exceeds a certain threshold, an action potential is generated and sent down the axon, where it reaches the next synapse via the terminal buttons described below.

Vesicles containing materials such as proteins, lipids, sugars, and transmitter substances are conveyed from the Golgi complex of the soma to the terminal buttons and the tips of the dendrites by rapid axonal transport (40 cm/day). This type of anterograde transport along the neurotubules is promoted by kinesin, a myosin-like protein, and the energy required for it is supplied by ATP. Endogenous and exogenous substances such as nerve growth factor (NGF), herpes virus, poliomyelitis virus, and tetanus toxin are conveyed by retrograde transport from the peripheral regions to the soma at a rate of ca. 25 cm/day. Slow axon transport (1 mm/day) plays a role in the regeneration of severed neurites. Along the axon, the plasma membrane of the soma continues as the axolemma. The axolemma is surrounded by oligodendrocytes in the central nervous system (CNS), and by Schwann cells in the peripheral nervous system. A nerve fiber consists of an axon plus its sheath. In some neurons, Schwann cells form multiple concentric double phospholipid layers around an axon,comprising themyelin sheath that insulates the axon from ion currents. The sheath is interrupted every 1.5mm or so at the nodesof Ranvier. The conduction velocity of myelinated nerve fibers is much higher thanthat of unmyelinated nerve fibers and increases with the diameter of the nerve fiber. A synapse is the site where the axon of a neuron communicates with effectors or other neurons. With very few exceptions, synaptic transmissions in mammals aremediated by chemicals, not by electrical signals. In response to an electrical signal in the axon, vesicles on the presynaptic membrane release transmitter substances (neurotransmitters) by exocytosis. The transmitter diffuses across the synaptic cleft (10–40 nm) to the postsynaptic membrane, where it binds to receptors effecting new electrical changes. Depending on the type of neurotransmitter and postsynaptic receptor involved, the transmitter will either have an excitatory effect (e.g., acetylcholine in skeletal muscle) or inhibitory effect (e.g., glycine in the CNS) on the postsynaptic membrane. Since the postsynaptic membrane normally does not release neurotransmitters (with only few exceptions), nerve impulses can pass the synapse in one direction only. The synapse therefore acts like a valve that ensures the orderly transmission of signals. Synapses are also the sites at which neuronal signal transmissions can be modified by other (excitatory or inhibitory) neurons.

 

 

Resting Membrane Potential. An electrical potential difference, or membrane potential (Em), can be recorded across the plasma membrane of living cells. The potential of unstimulated muscle and nerve cells, or resting potential, amounts to – 50 to – 100mV (cell interior is negative). A resting potential is caused by a slightly unbalanced distribution of ions between the intracellular fluid (ICF) and extracellular fluid (ECF).The following factors are involved in establishing the membrane potential. Maintenance of an unequal distribution of ions: The Na+-K+-ATPase continuously “pumps” Na+ out of the cell and K+ into it. As a result, the intracellular K+ concentration is around 35 times higher and the intracellular Na+ concentration is roughly 20 times lower than the extracellular concentration. As in any active transport, this process requires energy, which is supplied by ATP. Lack of energy or inhibition of the Na+-K+-ATPase results in flattening of the ion gradient andbreakdown of the membrane potential. Because anionic proteins and phosphates present in high concentrations in the cytosol are virtually unable to leave the cell, purely passive mechanisms (Gibbs–Donnan distribution) could, to a slight extent, contribute to the unequal distribution of diffusable ions.

However, this has practically no effect on the development of resting potentials. Low resting Na+ and Ca2+ conductance, gNa, gCa: The membrane of a resting cell is only very slightly permeable to Na+ and Ca2+, and the resting gNa comprises only a small percentage of the total conductance. Hence, the Na+ concentration difference cannot be eliminated by immediate passive diffusion of Na+ back into the cell. ! High K+conductance, gK: It is relatively easy for K+ ions to diffuse across the cell membrane (gK 90% of total conductance). Because of the steep concentration gradient, K+ ions diffuse from the ICF to the ECF. Because of their positive charge, the diffusion of even small amounts of K+ ions leads to an electrical potential (diffusion potential) across the membrane. This (inside negative) diffusion potential drives K+ back into the cell and rises until large enough to almost completely compensate for the K+ concentration gradient driving the K+-ions out of the cell (!A4). As a result, the membrane potential, Em, is approximately equal to the K+ equilibrium potential EK. Cl– distribution: Since the cell membrane is also conductive to Cl– (gCl greater in muscle cells than ierve cells), the membrane potential (electrical driving “force”) expels Cl– ions from the cell until the Cl– concentration gradient (chemical driving “force”) drives them back into the cell at the same rate. The intracellular Cl– concentration, [Cl–]i, then continues to rise until the Cl– equilibrium potential equals Em. [Cl–]i can be calculated using the Nernst equation.

Such a “passive” distribution of Cl– between the intra- and extracellular spaces exists only as long as there is no active Cl– uptake into thecell.  Why is Em less negative than EK? Although the conductances of Na+ and Ca2+ are very low in resting cells, a few Na+ and Ca2+ ions constantly enter the cell. This occurs because the equilibrium potential for both typesof ions extends far into the positive range, resulting in a high outside-to-inside electrical and chemical driving “force” for these ions. This cation influx depolarizes the cell, thereby driving K+ ions out of the cell (1 K+ for each positive charge that enters). If Na+-K+-ATPase did not restore these gradients continuously (Ca2+ indirectly via the 3Na+/Ca2+ exchanger), the intracellular Na+ and Ca2+ concentrations would increase continuously, whereas [K+]i would decrease, and EK and Em would become less negative. All living cells have a (resting) membrane potential, but only excitable cells such as nerve and muscle cells are able to greatly change the ion conductance of their membrane in response to a stimulus, as in an action potential.

Skeletal muscle constitutes 40% of muscle mass. Derangement of muscle function can have profound systemic effects.

Physiological skeletal muscle contraction requires generation and spread of a membrane action potential, transduction of the electrical energy into an intracellular chemical signal that, in turn, triggers myofilament interaction.

Intracellular cytoskeletal proteins, cell membrane structures and the associated glycoprotein extracellular matrix are important for maintenance of cell architecture and force transmission.

Smooth and graded changes in force of contraction are achieved through summation of responses to successive stimuli and recruitment of motor units.

Sustained muscle contraction requires de novo synthesis of ATP, which is principally aerobic or anaerobic depending on muscle fibre type.

The skeletal muscles are the effector organs of the locomotor system. They are under voluntary control, although much of their activity is subconsciously regulated. Skeletal muscle and cardiac muscle are both described as striated muscle because of their striped microscopic appearance. This appearance results from the ordered and regular arrangement of the sub-cellular contractile elements. Unlike cardiac muscle, skeletal muscle has no intrinsic spontaneous activity because it lacks the ion channels responsible for spontaneous membrane depolarization. Therefore, the stimulus for physiological skeletal muscle activity is always derived from a nerve impulse. The great majority of skeletal muscle fibres receive their nerve inputs at single central swellings of the fibres known as motor endplates. A few muscles, notably some of the facial muscles, are more diffusely innervated along the length of their fibres; such multifocal innervation may explain why these muscles respond with a more pronounced initial increase in tension after administration of succinylcholine.

However, irrespective of the type of innervation, the charge density arriving at the motor nerve terminal is insufficient to directly activate the much larger muscle fibres. The electrical neuronal impulse is amplified at the neuromuscular junction, the mechanism of which is beyond the remit of this review. The resulting generation of the endplate potential is the first step in muscle contraction.

Transmission from nerve to muscle resembles chemical synaptic transmission. The myoneural junction, the specialized area where a motor nerve terminates on a skeletal muscle fiber, is the site of a stereotyped transmission process. The contacts between autonomic neurons and smooth and cardiac muscle are less specialized, and transmission is a more diffuse process.)

a) Classification of synapses (For localization – central (neuro-neuronal) and peripheral (neuro-muscles, neuro-secretion; central synapses may be axo-somatic, axo-dendrites, axo-axonal, dendro-dendrites; for functional meaning – excitatory and inhibitory; for the method of transmission – electrical and chemical.

There is considerable variation in the anatomic structure of synapses in various parts of the mammaliaervous system. The ends of the presynaptic fibers are generally enlarged to form terminal buttons (synaptic knobs). Endings are commonly located on dendritic spines, which are small knobs projecting from dendrites. In some instances, the terminal branches of the axon of the presynaptic neuron form a basket or net around the soma of the postsynaptic cell (“basket cells” of the cerebellum and autonomic ganglia). In other locations, they intertwine with the dendrites of the postsynaptic cell (climbing fibers of the cerebellum) or end on the dendrites directly (apical dendrites of cortical pyramids) or on the axons (axo-axonal endings). In the spinal cord, the presynaptic endings are closely applied to the soma and the proximal portions of the dendrites of the postsynaptic neuron. The number of synaptic knobs varies from one per postsynaptic cell (in the midbrain) to a very large number. The number of synaptic knobs applied to a single spinal motor neuron has been calculated to be about 10,000, with 2000 on the cell body and 8000 on the dendrites. Indeed, there are so many knobs that the neuron appears to be encrusted with them. The portion of the soma membrane covered by any single synaptic knob is small, but the synaptic knobs are so numerous that, in aggregate, the area covered by them all is often 40 % of the total membrane area. In the cerebral cortex, it has been calculated that 98 % of the synapses are on dendrites and only 2 % are on cell bodies.)

b) Figure 6, Structure of synapses (All synapses consist of: presynaptic membrane, postsynaptic membrane, synaptic cleft, subsynaptic membrane.)

 

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c) Excitatory postsynaptic porential (Single stimuli applied to the sensory nerves in the experimental situation described above characteristically do not lead to the formation of a propagated action potential in the postsynaptic neuron. Instead, the stimulation produces either a transient, partial depolarization or a transient hyperpolarization.

The depolarizing response produced by a single stimulus to the proper input begins about 0,5 ms after the afferent impulse enters the spinal cord. It reaches its peak 1-1,5 ms later and then declines exponentially, with a time constant (time required for the response to decay to 1/e, or 1/2,718 of its maximum) of about 4 ms. During this potential, the excitability of the neuron to other stimuli is increased, and consequently the potential is called an excitatory postsynaptic potential (EPSP).

The EPSP is due to depolarization of the postsynaptic cell membrane immediately under the active synaptic knob. The area of inward current flow thus created is so small that it will not drain off enough positive charges to depolarize the whole membrane. Instead, an EPSP is inscribed. The EPSP due to activity in one synaptic knob is small, but the depolarizations produced by each of the active knobs summate.

Summation may be spatial or temporal. When activity is present in more than one synaptic knob at the same time, spatial summation occurs and activity in one synaptic knob is said to facilitate activity in another to approach the firing level. Temporal summation occurs if repeated afferent stimuli cause new EPSPs before previous EPSPs have decayed. The EPSP is therefore not an all or none response but is proportionate in size to the strength of the afferent stimulus. If the EPSP is large enough to reach the firing level of the cell, a full-fledged action potential is produced.)

d) Synaptic delay (When an impulse reaches the presynaptic terminals, there is an interval of at least 0,5 ms, the synaptic delay, before a response is obtained in the postsynaptic neuron. The delay following maximal stimulation of the presynaptic neuron corresponds to the latency of the EPSP and is due to the time it takes for the synaptic mediator to be released and to act on the membrane of the postsynaptic cell. Because of it, conduction along a chain of neurons is slower if there are many synapses in the chain than if there are only a few. This fact is important in comparing, for example, transmission in the lemniscal sensory pathways to the cerebral cortex and transmission in the reticular activating system. Since the minimum time for transmission across one synapse is 0,5 ms, it is also possible to determine whether a given reflex pathway is monosynaptic or polysynaptic (contains more than one synapse) by measuring the delay in transmission from the dorsal to the ventral root across the spinal cord.)

A synapse, or synaptic cleft, is the gap that separates adjacent neurons or a neuron and a muscle. Transmission of an impulse across a synapse, from presynaptic cell to postsynaptic cell, may be electrical or chemical. In electrical synapses, the action potential travels along the membranes of gap junctions, small tubes of cytoplasm along the membranes of gap junctions, small tubes of cytoplasm that allow the transfer of ions between adjacent cells. In chemical synapses, action potentials are transferred across the synapse by the diffusion of chemicals, as follows:

• Calcium (Ca²⁺) gates open. When an action potential reaches the end of an axon, the depolarization of the membrane causes gated channels to open that allow Ca²⁺ to enter.

• Synaptic vesicles release neurotransmitter. The influx of Ca²⁺ into the terminal end of the axon causes synaptic vesicles to merge with the presynaptic membrane, releasing a neurotransmitter into the synaptic cleft.

• Neurotransmitter binds with postsynaptic receptors. The neurotransmitter diffuses across the synaptic cleft and binds with specialized protein receptors on the postsynaptic membrane. Different proteins are receptors for different neurotransmitters.

• The postsynaptic membrane is excited or inhibited. Depending upon the kind of neurotransmitter and the kind of membrane receptor, there are two possible outcomes for the postsynaptic membrane, both of which are graded potentials.

• If positive ion gates open (which allow more Na⁺ and Ca²⁺ to enter than K⁺ to exit), the membrane becomes depolarized, which results in an excitatory postsynaptic potential (EPSP). If the threshold potential is exceeded, an action potential is generated.

• If K⁺ or chlorine ion (Cl⁻) gates open (allowing K⁺ to exit or Cl⁻ to enter), the membrane becomes more polarized (hyperpolarized), which results in an inhibitory postsynaptic potential (IPSP). As a result, it becomes more difficult to generate an action potential on this membrane.

• The neurotransmitter is degraded and recycled. After the neurotransmitter binds to the postsynaptic membrane receptors, it is either transported back to and reabsorbed by the secreting neuron, or it is broken down by enzymes in the synaptic cleft. For example, the commoeurotransmitter acetylcholine is broken down by cholinesterase. Reabsorbed and degraded neurotransmitters are recycled by the presynaptic cell.

 

Common characteristic of electrical synapses (Electrical synapses is the junctions in which the transmission of information do through the direct passage of bioelectrical signal from cell to cell. This synapses has small synaptic split (to 5 nm), low specific resistance between the presynaptic and postsynaptic membranes. There are the transverse canals in both membranes with the diameter of 1 nm..)

a) Excitatory transmitter (Excitatory impulses go to the synapse and increase permeability of postsynaptic cell membrane to Na⁺.)

b) Inhibitory transmitter (Inhibitory impulses go to the synapse and increase permeability of postsynaptic cell membrane to Cl^–, not to Na⁺.)

 

Common characteristic of chemical synapses (Chemical synapses is the junctions in which the transmission of information do through the direct passage with chemical substances from cell to cell. These substances named mediators.)

a) Classification of chemical synapses (These synapses named for the type of mediator – cholinergic (mediator – acetylcholine), adrenergic (mediator – epinephrine, norepinephrine), serotonin (mediator – serotonin), dopaminenergic (mediator – dopamin), GABA-ergic (mediator – gamma-aminobutyric acid).

b) Chemical transmission of synaptic activity (Active membrane potential go along the nerve to presynaptic end – presynaptic membrane have depolarilazed – the Ca^2+-cannals activated – Ca^2+-go to the presynaptic end – Ca^2+-activated transport of vesiccles with the mediator along the neurofilaments to presynaptic membrane – the mediator pick out from presynaptic ends to the synaptic split – molecules of mediator diffuse through the synaptic split to postsynaptic membrane – molecules of mediator interact with the receptors on the postsynaptic membrane – this interaction lead to the conformation of receptors and activation of corresponding substances.)

Connective Tissue

A summary of the various kinds of connective tissues is given in Figure 1 and Table 1 . Some general characteristics of connective tissues follow.

 

TABLE 1 Kinds of Connective Tissue   Tissue Type Cells Present Fibers Present Matrix Characteristics Loose Connective Tissue:     areolar fibroblasts macrophages adipocytes mast cells plasma cells collagen elastic reticular loosely arranged fibers in gelatinous ground substance adipose adipocytes reticular collagen closely packed cells with a small amount of gelatinous ground substance; stores fat reticular reticular cells reticular loosely arranged fibers in gelatinous ground substance Dense Connective Tissue:       dense regular fibroblasts collagen (some elastic) parallel-arranged bundles of fibers with few cells and little ground substance; great tensile strength dense regular fibroblasts collagen (some elastic) Irregularly arranged bundles of fibers with few cells and little ground substance; high tensile strength Cartilage:       hyaline (gristle) chondrocytes collagen (some elastic) limited ground substance; dense, semisolid matrix fibrocartilage chondrocytes collagen (some elastic) limited ground intermediate between hyaline cartilage and dense connective tissue elastic chondrocytes elastic limited ground substance; flexible but firm matrix Bone (osseous tissue):       compact (dense) osteoblasts osteocytes collagen rigid, calcified ground substance with (canal systems) spongy (cancellous) osteoblasts osteocytes collagen rigid, calcified ground substance (no osteons) Blood & Lymph (vascular tissue):       blood erythrocytes leukocytes thrombocytes “fibers” are soluble proteins that form during clotting “matrix” is liquid blood plasma lymph leukocytes “fibers” are soluble liquid proteins that form during clotting “matrix” is blood plasma

 

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Functionally-structures peculiarities of nervous system Figure 7.

a) Neuron as a structurally-functional unit (The bases of nervous system are neurons. They have body or soma and axons and dendrites. Physiological role of axons is transmition of neurons impulses from soma to other neurons or organs, the physiological role of dendrites is supplying of information to the neurons body. The axon hillock has a maximal excitability ieurons. Neuron may be in the rest condition (absent change of rest membrane potential) and active condition (may generate active potential), and inhibition condition (stop the impulses activity of the neuron).

Classification of nervous cells according to functioning meaning: 1) Sensory or afferent (to perceive irritation and transmit excitement in central nervous system); 2) Interneurons (to help spreading of excitement ieurons nets or act inhibition); 3) moving (motor or efferent) – to transmit the excitement to working organs.

Mediators help to connect the neurons. There are excitable (glutamine acid, acetylcholine) and inhibitory (gamma-ammino-butiric acid – GABA, glycin) mediators.

b) Axon transport (There are 2 kinds of axon transport: fast and slow. Fast transport provides transmition of mitochondria, vesicles with mediators. It speed is 250-400 mm per day. These transport stop when destroyed microtubules and neurofilaments and if absent in axon ATP and Ca²⁺. Fast transport may transmit substances from the neurons’ body (anterogrades transport) and to body (retrogrades transport). By help of fast anterogrades transport transmit substances and structures which very important for synaptic action; by help of fast retrogrades transport moving trophogens, which need for nutritient of neurons, and products of axons’ metabolism. Slow axon transport is a transmition of all mass of cytoplasm in distal direction. It stops in the case of separation soma from axon. It need to axons’ growth and provide trophic in postsynaptic cells.)

c) Role of glia cells (The neurons of the central nervous system are supported by several varieties of non-excitable cells that are called the neuroglia. There are four types of neuroglial cells: astroglia, oligodendroglia, microglia, epindima. They have insulating function, produce myelin, have secretor role, absorbed from intercells fluid K⁺.)

 

Nervous tissue is composed of two main cell types: neurons and glial cells. Neurons transmit nerve messages. Glial cells are in direct contact with neurons and often surround them.

Nerve Cells and Astrocyte (SEM x2,250). This image is copyright Dennis Kunkel at, used with permission.

The neuron is the functional unit of the nervous system. Humans have about 100 billioeurons in their brain alone! While variable in size and shape, all neurons have three parts. Dendrites receive information from another cell and transmit the message to the cell body. The cell body contains the nucleus, mitochondria and other organelles typical of eukaryotic cells. The axon conducts messages away from the cell body.

Structure of a typical neuron.

Three types of neurons occur. Sensory neurons typically have a long dendrite and short axon, and carry messages from sensory receptors to the central nervous system. Motor neurons have a long axon and short dendrites and transmit messages from the central nervous system to the muscles (or to glands). Interneurons are found only in the central nervous system where they connect neuron to neuron.

Structure of a neuron and the direction of nerve message transmission.

 

Some axons are wrapped in a myelin sheath formed from the plasma membranes of specialized glial cells known as Schwann cells. Schwann cells serve as supportive, nutritive, and service facilities for neurons. The gap between Schwann cells is known as the node of Ranvier, and serves as points along the neuron for generating a signal. Signals jumping from node to node travel hundreds of times faster than signals traveling along the surface of the axon. This allows your brain to communicate with your toes in a few thousandths of a second.

 

 

Cross section of myelin sheaths that surround axons

Structure of a nerve bundle.

The Nerve Message

The plasma membrane of neurons, like all other cells, has an unequal distribution of ions and electrical charges between the two sides of the membrane. The outside of the membrane has a positive charge, inside has a negative charge. This charge difference is a resting potential and is measured in millivolts. Passage of ions across the cell membrane passes the electrical charge along the cell. The voltage potential is -65mV (millivolts) of a cell at rest (resting potential). Resting potential results from differences between sodium and potassium positively charged ions and negatively charged ions in the cytoplasm. Sodium ions are more concentrated outside the membrane, while potassium ions are more concentrated inside the membrane. This imbalance is maintained by the active transport of ions to reset the membrane known as the sodium potassium pump. The sodium-potassium pump maintains this unequal concentration by actively transporting ions against their concentration gradients.

Transmission of an action potential.

Changed polarity of the membrane, the action potential, results in propagation of the nerve impulse along the membrane. An action potential is a temporary reversal of the electrical potential along the membrane for a few milliseconds. Sodium gates and potassium gates open in the membrane to allow their respective ions to cross. Sodium and potassium ions reverse positions by passing through membrane protein channel gates that can be opened or closed to control ion passage. Sodium crosses first. At the height of the membrane potential reversal, potassium channels open to allow potassium ions to pass to the outside of the membrane. Potassium crosses second, resulting in changed ionic distributions, which must be reset by the continuously running sodium-potassium pump. Eventually enough potassium ions pass to the outside to restore the membrane charges to those of the original resting potential.The cell begins then to pump the ions back to their original sides of the membrane.

The action potential begins at one spot on the membrane, but spreads to adjacent areas of the membrane, propagating the message along the length of the cell membrane. After passage of the action potential, there is a brief period, the refractory period, during which the membrane cannot be stimulated. This prevents the message from being transmitted backward along the membrane.

Steps in an Action Potential

1.     At rest the outside of the membrane is more positive than the inside.

2.     Sodium moves inside the cell causing an action potential, the influx of positive sodium ions makes the inside of the membrane more positive than the outside.

3.     Potassium ions flow out of the cell, restoring the resting potential net charges.

4.     Sodium ions are pumped out of the cell and potassium ions are pumped into the cell, restoring the original distribution of ions.

Synapses

The junction between a nerve cell and another cell is called a synapse. Messages travel within the neuron as an electrical action potential. The space between two cells is known as the synaptic cleft. To cross the synaptic cleft requires the actions of neurotransmitters. Neurotransmitters are stored in small synaptic vessicles clustered at the tip of the axon.

 

 

 

                                             

 

                     A synapse.

Excitatory Synapse from the Central Nervous System.

Arrival of the action potential causes some of the vesicles to move to the end of the axon and discharge their contents into the synaptic cleft. Released neurotransmitters diffuse across the cleft, and bind to receptors on the other cell’s membrane, causing ion channels on that cell to open. Some neurotransmitters cause an action potential, others are inhibitory.

Neurotransmitters tend to be small molecules, some are even hormones. The time for neurotransmitter action is between 0,5 and 1 millisecond. Neurotransmitters are either destroyed by specific enzymes in the synaptic cleft, diffuse out of the cleft, or are reabsorbed by the cell. More than 30 organic molecules are thought to act as neurotransmitters. The neurotransmitters cross the cleft, binding to receptor molecules on the next cell, prompting transmission of the message along that cell’s membrane. Acetylcholine is an example of a neurotransmitter, as is norepinephrine, although each acts in different responses. Once in the cleft, neurotransmitters are active for only a short time. Enzymes in the cleft inactivate the neurotransmitters. Inactivated neurotransmitters are taken back into the axon and recycled.

Diseases that affect the function of signal transmission can have serious consequences. Parkinson’s disease has a deficiency of the neurotransmitter dopamine. Progressive death of brain cells increases this deficit, causing tremors, rigidity and unstable posture. L-dopa is a chemical related to dopamine that eases some of the symptoms (by acting as a substitute neurotransmitter) but cannot reverse the progression of the disease.

The bacterium Clostridium tetani produces a toxin that prevents the release of GABA. GABA is important in control of skeletal muscles. Without this control chemical, regulation of muscle contraction is lost; it can be fatal when it effects the muscles used in breathing.

Clostridium botulinum produces a toxin found in improperly canned foods. This toxin causes the progressive relaxation of muscles, and can be fatal. A wide range of drugs also operate in the synapses: cocaine, LSD, caffeine, and insecticides.

 

Nervous Systems

Multicellular animals must monitor and maintain a constant internal environment as well as monitor and respond to an external environment. In many animals, these two functions are coordinated by two integrated and coordinated organ systems: the nervous system and the endocrine system. Click here for a diagram of the Nervous System.

Three basic functions are prformed by nervous systems:

1.     Receive sensory input from internal and external environments

2.     Integrate the input

3.     Respond to stimuli

Sensory Input

Receptors are parts of the nervous system that sense changes in the internal or external environments. Sensory input can be in many forms, including pressure, taste, sound, light, blood pH, or hormone levels, that are converted to a signal and sent to the brain or spinal cord.

Integration and Output

In the sensory centers of the brain or in the spinal cord, the barrage of input is integrated and a response is generated. The response, a motor output, is a signal transmitted to organs than can convert the signal into some form of action, such as movement, changes in heart rate, release of hormones, etc.

Endocrine Systems

Some animals have a second control system, the endocrine system. The nervous system coordinates rapid responses to external stimuli. The endocrine system controls slower, longer lasting responses to internal stimuli. Activity of both systems is integrated.

Divisions of the Nervous System

The nervous system monitors and controls almost every organ system through a series of positive and negative feedback loops.The Central Nervous System (CNS) includes the brain and spinal cord. The Peripheral Nervous System (PNS) connects the CNS to other parts of the body, and is composed of nerves (bundles of neurons).

Not all animals have highly specialized nervous systems. Those with simple systems tend to be either small and very mobile or large and immobile. Large, mobile animals have highly developed nervous systems: the evolution of nervous systems must have been an important adaptation in the evolution of body size and mobility.

Coelenterates, cnidarians, and echinoderms have their neurons organized into a nerve net. These creatures have radial symmetry and lack a head. Although lacking a brain or either nervous system (CNS or PNS) nerve nets are capable of some complex behavior.

Nervous systems in radially symmetrical animals.

 

Bilaterally symmetrical animals have a body plan that includes a defined head and a tail region. Development of bilateral symmetry is associated with cephalization, the development of a head with the accumulation of sensory organs at the front end of the organism. Flatworms have neurons associated into clusters known as ganglia, which in turn form a small brain. Vertebrates have a spinal cord in addition to a more developed brain.

Some nervous systems in bilaterally symmetrical animals.

 

Chordates have a dorsal rather than ventral nervous system. Several evolutionary trends occur in chordates: spinal cord, continuation of cephalization in the form of larger and more complex brains, and development of a more elaborate nervous system. The vertebrate nervous system is divided into a number of parts. The central nervous system includes the brain and spinal cord. The peripheral nervous system consists of all body nerves. Motor neuron pathways are of two types: somatic (skeletal) and autonomic (smooth muscle, cardiac muscle, and glands). The autonomic system is subdivided into the sympathetic and parasympathetic systems.

Definition of speed conduction of excitation by moving nerve:

To establish stimulating electrodes over the nervus ulnaris more medial to processus ulnaris. The leading electrodes place over the abducens muscle of fifth finger. Inflict the upper threshold stimulus.

On the electromyograph‘s screen to definite the time from moment of infliction of stimulus to moment of origin the active potential (latent period) – t₁. To carry stimulating electrodes in distant place and definite this latent period – t₂. To measure the distance between the places of stimulating electrodes – S.

The speed‘s conduction of excitation which are moving by nerve determine according to the formula: V=S: (t₁-t₂) (m/s).

Evaluation of neuro-muscular transmission:

To establish stimulating electrodes on the forearm (antebrachium) over the nervus ulnaris. The leading electrodes place over the muscle flexion wrist ulnar. Inflict the upper threshold stimulus with the gradual increasing of frequency to 70 impulses per second. On the electromyograph‘s screen look after the changing of amplitude of active membrane potential.

Space summation of under threshold stimulation:

To establish stimulating electrodes on the project of m. flexor carpi radialis in the middle third of antebrachii with the common square 1,2 sm². To establish level of threshold stimulus, which elicit prolonged contraction of muscle.

After that on this muscle put the electrodes with common square 4,0 sm². Inflict the under threshold stimulus that was for electrodes with the common square 1,2 sm².

 

Peculiarities of excitement transmition ieural chain.

a) Divergence and irradiation (Neurons may to connected by synapses with different nervous cells. This property has the notion divergence. If it will be an active transmition of excitement it is called irradiation.)

b) Convergence (On the each neuron of central nervous system may come together different afferent impulses. That is why in one neuron coming at the same time different excitement. Later it analyzing and formed in one axon excitement that goes to other chain of nervous net.)

c) Reverberation (In central nervous system are present the nervous chain of own excitement. They arise at the answer of stimulus and excitements in these chains are circulated to the time, when other external stimulus inhibits it or it tired. Reverberation is a base of short-time memory.)

d) Time summation (It is a rise of excitement in the case of action under threshold stimulus. If the frequency of stimulus sufficiently big, excitive postsynaptic potential amount to firing level of depolarization and active potential arise.)

e) Space summation (It is a rise of excitement because of simultaneous action of several under-threshold stimuli. In these cases excitive postsynaptic potential amount to the firing level of depolarization or may be more and active potential arise.)

f) Occlusion (On account of divergence one neuron may pass excitive signals on the other neurons. Another neuron may excite several neurons. But if from both neurons which is divergented excitement will be simultaneously the total quantity of excited neurons will be decrease.)

 

Inhibition in the nervous system (Inhibition is an active reaction which add to the oppression or prevention of excitement.)

a) Postsynaptic inhibition (Excitement, which are coming to the inhibitory neuron – Renshow cell of spinal cord, Purkinje cell of cerebellum, astrocites of cortex of big hemisphere – help to produce an inhibitory mediator of this cell (GABA, glycin). According to this act, increase activity of K⁺ channels of postsynaptic cells, which lead to the hyperpolarization. As result – decrease of activity of Na⁺ channels and possibility of development of depolarization in the excitive cell.)

b) Presynaptic inhibition (It may be between axons of excitive and inhibitory neurons. Inhibitory mediator cause hyperpolarization of axon of excitable neuron, prevent arriving of active potential to presynaptic end and as result decrease production of mediator for the development of excitement in postsynaptic cell.)

c) Opposite inhibition (Collaterals of axons of excitive nervous cells are form synaptic connection with inhibitory neurons. These inhibitory neurons have synaptic connection with these excitive neurons. In the case of excitement of excitive neuron activated inhibitory neuron, which produce GABA or glycin in synaptic cleft. As a result, occur hyperpolarization of membrane of excitive neuron and it activity inhibited. Opposite inhibition may be presynaptic or postsynaptic.)

d) Lateral inhibition (If in a neurons’ chain, which secure opposite inhibition collaterals of axons of inhibitioeurons form synaptic connection with neighboring excitive cells in these cells develop lateral inhibition.)

Common characteristic of reflexes (Reflex is a change of functional activity of tissues, organs or whole organism as an answer on stimulus by help of central neural system.)

a) Structure of reflector arc (Reflector arc is a structure base of reflex. It consists of 1. Receptors, which are perceive different influences which are act on organism; 2. Afferent neurons, which connect receptors with central nervous system; 3. Central part of central nervous system, which realize analyses and synthesis of afferent information; 4. Efferent chain secure going out of excitement from central nervous system; 5. Effector is executive organ; 6. Opposite connection.)

b) Classification of reflexes (1. According to the biological meaning: food, defensive, oriental, homeostatic, sex. 2. According to the position of receptors: exteroreceptors (skin, vision, hearing, smell), interoreceptors (visceroreceptors –from inner organs) and proprioreceptors (from muscular, tendons, joints). 3. According to the level of close of reflector arc: spinal, bulbar, mesencephalon, diencephalon, cortex. 4. According to the character of answer: moving, secretory, vessel-moving. 5. According to the duration of answer: fase, tonic. 6. According to the quantity of synapses in central chain: monosynaptic, polisynaptic. 7. According to the kind of efferent part of reflectory arc: somatic, autonomic. 8. According to the position of effector: moving, vessels, heart, secretory, etc. 9. According to the adaptative meaning: physiological, pathological.)