General Physiology Chapter 4 2nd Year Med 2024-2025 PDF

Lebanese University Faculty of Medical Sciences Hadath campus General Physiology 2nd Medical Educational year Academic year: 2024 – 2025 Prepared by: Dr. Ghenwa NASR  Chapter 4: The Nervous System 2 Chapter Outline 1. Neural Tissue 1.1. Stru...

Lebanese University Faculty of Medical Sciences Hadath campus General Physiology 2nd Medical Educational year Academic year: 2024 – 2025 Prepared by: Dr. Ghenwa NASR  Chapter 4: The Nervous System 2 Chapter Outline 1. Neural Tissue 1.1. Structure and Maintenance of Neurons 1.2. Functional and Structural Classes of Neurons 1.3. Glial Cells 1.4. Neural Growth and Regeneration 2. Membrane Potentials 2.1. Basic Principles of Electricity 2.2. The Resting Membrane Potential 2.3. Graded Potentials and Action Potentials 3. Synapses 3.1. Functional Anatomy of Synapses 3.2. Mechanisms of Neurotransmitter Release 3.3. Activation of the Postsynaptic Cell 3.4. Synaptic Integration 3.5. Synaptic Strength 3.6. Neurotransmitters and Neuromodulators 3.7. Neuroeffector Communication 4. Structures et Fonctions du Système Nerveux 4.1. Overview of the Central Nervous System and the Peripheral Nervous System 4.2. Autonomic Nervous System: Role, Function and Receptors in play 3 1. Neural Tissue The nervous system is a network of neurons whose main feature is to generate, modulate and transmit information between all the different parts of the human body. Thisproperty enables many important functions of the nervous system, such as regulation of vital body functions (heartbeat, breathing, digestion), sensation and body movements. Ultimately, the nervous system structures preside over everything that makes us human; our consciousness, cognition, behavior and memories. The nervous system is one of the two regulatory systems in the human body that influences the activity of all the other organ systems. It consists of billions of neurons interconnected in a highly organized manner to form circuits. 4 1. Neural Tissue The nervous system consists of two divisions: (1) The central nervous system (CNS), composed of the brain and spinal cord which are enclosed and protected by the cranium and vertebral column. It is the integration and command center of the body; (2) The peripheral nervous system (PNS), consisting of the nerves that connect the brain and spinal cord with the body’s muscles, glands, sense organs, and other tissues. The neural tissue or the nervous tissue is the main tissue component of the nervous system which regulates and controls the body functions and activity. Neural tissue consists of two types of cells: 1. Neurons which transmits nerve impulses 2. Glial cells which support and nourish neurons. Neural tissue is found in the brain, the spinal cord and the peripheral nerves. 5 1. Neural Tissue 1.1. Structure and Maintenance of Neurons The functional unit of the nervous system is the individual cell, or neuron. Neurons operate by generating electrical signals that move from one part of the cell to another part of the same cell or to neighboring cells. In most neurons, the electrical signal causes the release of chemical messengers called neurotransmitters to communicate with other cells. Most neurons serve as integrators because their output reflects the balance of inputs they receive from up to hundreds of thousands of other neurons. 6 1. Neural Tissue 1.1. Structure and Maintenance of Neurons Neurons occur in a wide variety of sizes and shapes, but all share common features that allow cell-to-cell communication. Most neurons contain a cell body and two types of processes: dendrites and axons. A neuron’s cell body (or soma) contains the nucleus and different cellular organelles such as ribosomes and thus, it has the genetic information and machinery necessary for protein synthesis. Long extensions, or processes, connect neurons to each other and perform the neurons’ input and output functions. There are two types of neural processes that differ in structure and function : 1. The dendrites: ✓ They are short processes; they are a series of highly branched outgrowths of the cell that receive incoming information from other neurons conducting the electrical signal towards the nerve cell body. 7 1. Neural Tissue 1.1. Structure and Maintenance of Neurons ✓ Branching dendrites increase a cell’s surface area; some CNS neurons may have as many as 400 000 dendrites. ✓ Knoblike outgrowths called dendritic spines increase the surface area of dendrites still further. Thus, the structure of dendrites in the CNS increases a cell’s capacity to receive signals from many other neurons. ✓ Dendritic spines are small membranous protrusions from a neuron’s dendrite that typically receive input from a single axon at the synapse. 8 1. Neural Tissue 1.1. Structure and Maintenance of Neurons 2. Axons ✓ The axon is a long process that extends from the cell carries outgoing signals away from the neuronal body to its target cells body. In humans, axons range in length from a few microns to over a meter. ✓ The region of the axon that arises from the cell body is known as the axon hillock (or initial segment). The axon hillock is the location where, in most neurons, propagated electrical signals are generated. These signals then propagate away from the cell body along the axon. 9 1. Neural Tissue 1.1. Structure and Maintenance of Neurons 2. Axons ✓ The axon may have branches, called collaterals. Near their ends, both the axon and its collaterals undergo further branching. ✓ Each branch ends in an axon terminal, which is responsible for releasing neurotransmitters from the axon. 10 1. Neural Tissue 1.1. Structure and Maintenance of Neurons 2. Axons ✓ Some neurons release their chemical messengers from a series of bulging areas along the axon known as varicosities. The varicosities, or swellings, act as points of contact with other cells such as smooth muscle fibers. 11 1. Neural Tissue 1.1. Structure and Maintenance of Neurons The Myelin Sheaths ✓ The axons of many neurons are covered by sheaths of myelin, which usually consists of 20 to 200 layers of highly modified plasma membrane wrapped around the axon by a nearby supporting cell called “the myelin- forming cell”. ✓ There are two types of myelin-forming cells: the oligodendrocytes and the Schwann cells. Theses two are glial cells. 12 1. Neural Tissue 1.1. Structure and Maintenance of Neurons The Myelin Sheaths ✓ In the brain and spinal cord (CNS), these myelin-forming cells are a type of glial cell called oligodendrocytes. Each oligodendrocyte may branch to form myelin on as many as 40 axons. ✓ In the PNS, glial cells called Schwann cells form individual myelin sheaths surrounding 1- to 1.5-mm-long segments at regular intervals along some axons. ✓ Thespaces between adjacent sections of myelin where the axon’s plasma membrane is exposed to extracellular fluid are called the nodes of Ranvier. The myelin sheath speeds up conduction of the electrical signals along the axon, conserves energy and insulate axons. 13 1. Neural Tissue 1.1. Structure and Maintenance of Neurons The Axonal Transport To maintain the structure and function of the axon, various organelles and other materials must move between the cell body and the axon terminals. This transport is termed “the axonal transport”. Axonal transport, also called axoplasmic transport, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplasm of its axon. Since some axons are on the order of meters long, neurons cannot rely on diffusion to carry products of the nucleus and organelles to the end of their axons. Axonal transport is also responsible for moving molecules destined for degradation from the axon back to the cell body, where they are broken down by lysosomes. The axonal transport is achieved in two directions: from the cell body to the axon’s end and in the opposite direction. 14 1. Neural Tissue 1.1. Structure and Maintenance of Neurons The Axonal Transport This movement depends on a scaffolding of microtubule “rails” running the length of the axon and specialized types of motor proteins known as kinesins and dyneins. At one end, these double-headed motor proteins (kinesins or dyneins) bind to their cellular cargo, and the other end uses energy derived from the hydrolysis of ATP to “walk” along the microtubules. This figure shows how small “motor molecules” attach to mitochondria and vesicles containing neurotransmitters and carry them to the end of the axon. The “used” vesicles and transmitters are then returned to the cell body by the same process, but in reverse, for recycling. Two types of axonal transport can be identified: the retrograde transport and the anterograde transport. 15 1. Neural Tissue 1.1. Structure and Maintenance of Neurons The Axonal Transport Kinesin transport mainly occurs from the cell body toward the axon terminals; this type of transport is termed the anterograde transport. It is important in moving nutrient molecules, enzymes, mitochondria, neurotransmitter-filled vesicles, and other organelles. Dynein movement is in the other direction: from the axonal terminal to the cell body; it is termed the retrograde transport, carrying recycled membrane vesicles, growth factors, and other chemical signals that can affect the neuron’s morphology, biochemistry, and connectivity. Retrograde transport is also the route by which some harmful agents invade the CNS, including tetanus toxin and the herpes simplex, rabies, and polio viruses. Axonal transport along microtubules by dynein and kinesin. 16 1. Neural Tissue 1.2. Functional and Structural Classes of Neurons Neurons can be divided into three functional classes: afferent neurons, efferent neurons, and interneurons. Afferent neurons (or sensory neurons) convey or transmit information from the tissues and organs of the body toward the CNS. Efferent neurons (or motor neurons) convey or transmit information away from the CNS to effector cells like muscle, gland, or other cell types. Interneurons (or association neurons) connect neurons within the CNS. They integrate the information and generate a response. As a rough estimate, for each afferent neuron entering the CNS, there are 10 efferent neurons and 200,000 interneurons. Thus, the great majority of neurons are interneurons. 17 1. Neural Tissue 1.2. Functional and Structural Classes of Neurons At their peripheral ends, afferent neurons have sensory receptors, which respond to various physical or chemical changes in their environment by generating electrical signals in the neuron. Afferent neurons propagate electrical signals from their receptors into the brain or spinal cord. At their peripheral ends, efferent neurons are connected to effectors such as muscles and glands that execute the response. 18 1. Neural Tissue 1.2. Functional and Structural Classes of Neurons 19 1. Neural Tissue 1.2. Functional and Structural Classes of Neurons Afferent neurons have only a single process associated with the cell body, usually considered an axon. Shortly after leaving the cell body, the axon divides. One branch, the peripheral process, begins where the afferent terminal branches converge from the receptor endings. The other branch, the central process, enters the CNS to form junctions with other neurons. For afferent neurons, both the cell body and the long axon are outside the CNS and only a part of the central process enters the brain or spinal cord. Efferent neurons have their cell bodies and dendrites within the CNS, and the axons extend out to the periphery (with some exceptions). Interneurons lie entirely within the CNS. They account for over 99% of all neurons and have a wide range of physiological properties, shapes, and functions. The number of interneurons interposed between specific afferent and efferent neurons varies according to the complexity of the action they control. 20 1. Neural Tissue 1.2. Functional and Structural Classes of Neurons The junction between two neurons is called a synapse. At most synapses, the signal is transmitted from one neuron to another by neurotransmitters, a term that also includes the chemicals efferent neurons use to communicate with effector cells (e.g., a muscle cell). The neurotransmitters released from one neuron alter the receiving neuron by binding with specific protein receptors on the membrane of the receiving neuron. Most synapses occur between an axon terminal of one neuron and a dendrite or the cell body of a second neuron. A neuron that conducts a signal toward a synapse is called a presynaptic neuron, whereas a neuron conducting signals away from a synapse is a postsynaptic neuron. In a multi-neuronal pathway, a single neuron can be postsynaptic to one cell and presynaptic to another (check figure). A postsynaptic neuron may have thousands of synaptic junctions on the surface of its dendrites and cell body, so that signals from many presynaptic neurons can affect it. 21 1. Neural Tissue 1.3. Glial Cells Neurons account for only about half of the cells in the human CNS. The remainder are glial cells (glia, “glue”). Glial cells surround the axon and dendrites of neurons, and provide them with physical and metabolic support. Unlike most neurons, glial cells retain the capacity to divide throughout life. Consequently, many CNS tumors actually originate from glial cells rather than from neurons. There are different types of glial cells found in the CNS: ✓ Oligodendrocytes ✓ Astrocytes ✓ Microglia ✓ Ependymal cells In the PNS, Schwann cells are the glial cells. 22 1. Neural Tissue 1.3. Glial Cells Oligodendrocytes: The oligodendrocyte forms the myelin sheath of CNS axons, as mentioned earlier. Astrocytes They help regulate the composition of the extracellular fluid in the CNS by removing potassium ions and neurotransmitters around synapses. They stimulate the formation of tight junctions between the cells that make up the walls of capillaries found in the CNS. This forms the blood–brain barrier, which is a much more selective filter for exchanged substances than is present between the blood and most other tissues. 23 1. Neural Tissue 1.3. Glial Cells Astrocytes are involved in the formation of the tight junctions between endothelial cells of the blood vessel in the brain 24 1. Neural Tissue 1.3. Glial Cells Astrocytes Astrocytes also sustain the neurons metabolically by providing glucose and removing the secreted metabolic waste product ammonia. In embryos, astrocytes guide CNS neurons as they migrate to their ultimate destination, and they stimulate neuronal growth by secreting growth factors. Astrocytes have many neuronlike characteristics: they have ion channels, receptors for certain neurotransmitters and the enzymes for processing them, and the capability of generating weak electrical responses. Thus, astrocytes may take part in information signaling in the brain. 25 1. Neural Tissue 1.3. Glial Cells Microglia Microglia are specialized, macrophage-like cells that perform immune functions in the CNS. They may also contribute to synapse remodeling and plasticity. Ependymal cells The ependymal cells line the fluid-filled cavities within the brain and spinal cord and regulate the production and flow of cerebrospinal fluid. Schwann cells Schwann cells, the glial cells of the PNS, have most of the properties of the CNS glia. As mentioned earlier, Schwann cells produce the myelin sheath of the axons of the peripheral neurons. 26 1. Neural Tissue 1.3. Glial Cells Glial cells of the CNS 27 1. Neural Tissue 1.4. Neural Growth and Regeneration Growth and Development of Neurons Neuronal development is the biological process by which neurons are produced during development. The processes that contribute to neuronal development include proliferation, differentiation, migration, axon guidance and synapse formation. Development of the nervous system in the embryo begins with a series of divisions (mitosis) of undifferentiated precursor cells (stem cells) that can develop into neurons or glia. This is the first stage of the process: proliferation. After the last cell division, each neuronal daughter cell differentiates, migrates to its final location, and sends out processes that will become its axon and dendrites. A specialized enlargement, the growth cone, forms the tip of each extending axon and is involved in finding the correct route and final target for the process. 28 1. Neural Tissue 1.4. Neural Growth and Regeneration Growth and Development of Neurons As the axon grows, it is guided along the surfaces of other cells, most commonly glial cells. Which route the axon follows depends largely on attracting, supporting, deflecting, or inhibiting influences exerted by several types of molecules. Once the target of the advancing growth cone is reached, synapses form. During these early stages of neural development, which occur during all trimesters of pregnancy and into infancy, alcohol and other drugs, radiation, malnutrition, and viruses can exert effects that cause permanent damage to the developing fetal nervous system. 29 1. Neural Tissue 1.4. Neural Growth and Regeneration Growth and Development of Neurons A surprising aspect of development of the nervous system occurs after growth and projection of the axons: many of the newly formed neurons and synapses degenerate. In fact, as many as 50% to 70% of neurons undergo a programmed self-destruction called apoptosis in the developing CNS. Neuroplasticity or brain plasticity is the ability pf the brain to change and adapt in structure and function in response to learning, experience, stimuli or injury. It involves neurons making new connections or pathways, called synapses or weakening existing ones. The degree of neural plasticity varies with age. For example, the ability to learn a language undergoes a slow change in plasticity: humans learn languages relatively easily and quickly until adolescence, but learning becomes slower and more difficult as we proceed from adolescence through adulthood. Although it was previously thought that production of new neurons ceases around the time of birth, a growing body of evidence now indicates that the ability to produce new neurons is retained in some brain regions throughout life. For example, cognitive stimulation and exercise have both been shown to increase the number of neurons in brain regions associated with learning even in adults. In addition, the effectiveness of some antidepressant medications has been shown to depend upon the production of new neurons in regions involved in emotion and motivation. 30 1. Neural Tissue 1.4. Neural Growth and Regeneration Regeneration of Axons If axons are severed, they can repair themselves and restore significant function provided if the damage occurs outside the CNS and does not affect the neuron’s cell body. After such an injury, the axon segment that is separated from the cell body degenerates. The part of the axon still attached to the cell body then gives rise to a growth cone, which grows out to the effector organ so that function can be restored. 31 1. Neural Tissue 1.4. Neural Growth and Regeneration Regeneration of Axons Return of function following a peripheral nerve injury is delayed because axon regrowth proceeds at a rate of only about 1 mm per day. So, for example, if afferent neurons from your thumb were damaged by an injury in the area of your shoulder, it might take 2 years for sensation in your thumb to be restored. Spinal injuries typically crush rather than cut the tissue, leaving the axons intact. In this case, a primary problem is self-destruction (apoptosis) of the nearby oligodendrocytes. When these cells die and their associated axons lose their myelin sheath, the axons cannot transmit information effectively. Severed axons within the CNS may grow small new extensions, but no significant regeneration of the axon occurs across the damaged site, and there are no well-documented reports of significant return of function. Functional regeneration is prevented either by some basic difference of CNS neurons or some property of their environment, such as inhibitory factors associated with nearby glia. 32 2. Membrane Potentials 2.1. Basic Principles of Electricity The predominant solutes in the extracellular fluid ECF are sodium and chloride ions. The intracellular fluid contains high concentrations of potassium ions and ionized nonpenetrating molecules, particularly phosphate compounds and proteins with negatively charged side chains. Electrical phenomena resulting from the distribution of these charged particles occur at the cell’s plasma membrane and have a significant function in signal integration and cell-to- cell communication, the two major functions of the neuron. A fundamental physical principle is that charges of the same type repel each other: positive charge repels positive charge, and negative charge repels negative charge. In contrast, oppositely charged substances attract each (a) Types of electrical interactions. other and will move toward each other if not separated (b) Effects on electrical forces of quantity and by some barrier. distance between charges. 33 2. Membrane Potentials 2.1. Basic Principles of Electricity Separated electrical charges of opposite sign have the potential to do work if they are allowed to come together. This potential is called an electrical potential or, because it is determined by the difference in the amount of charge between two points, a potential difference (often referred to simply as the potential). The units of electrical potential are volts. The total charge that can be separated in most biological systems is very small, so the potential differences are small and are measured in millivolts (1 mV = 0.001 V). The movement of electrical charge is called a current. The electrical potential between charges tends to make them flow, producing a current. If the charges are opposite, the current brings them toward each other; if the charges are alike, the current increases the separation between them. The amount of charge that moves - in other words, the magnitude of the current - depends on the potential difference between the charges and on the nature of the material or structure through which they are moving. 34 2. Membrane Potentials 2.1. Basic Principles of Electricity The hindrance to electrical charge movement is known as resistance. If resistance is high, the current flow will be low. The effect of voltage V and resistance R on current I is expressed in Ohm’s law: 𝑉 𝐼 = 𝑅 Materials that have a high electrical resistance reduce current flow and are known as insulators. Materials that have a low resistance allow rapid current flow and are called conductors. Water that contains dissolved ions is a relatively good conductor of electricity because the ions can carry the current. As we have seen, the intracellular and extracellular fluids contain many ions and can therefore carry current. Lipids, however, contain very few charged groups and cannot carry current. Therefore, the lipid layers of the plasma membrane are regions of high electrical resistance separating the intracellular fluid and the extracellular fluid, two low-resistance aqueous compartments. 35 2. Membrane Potentials 2.2. The Resting Membrane Potential At rest, neurons have a potential difference across their plasma membranes, with the inside of the cell negatively charged with respect to the outside. This potential is the resting membrane potential (abbreviated Vm). By convention, extracellular fluid is designated as the voltage reference point, and the polarity (positive or negative) of the membrane potential is stated in terms of the sign of the excess charge on the inside of the cell by comparison. For example, if the inside of a cell has an excess of negative charge and the potential difference across the membrane has a magnitude of 70 mV, we say that the membrane potential is −70 mV (inside relative to outside). (a) Apparatus for measuring membrane potentials. The voltmeter records the difference between the intracellular and extracellular electrodes. (b) The potential difference across a plasma membrane as measured by an intracellular microelectrode. The asterisk indicates the moment the electrode entered the cell. 36 2. Membrane Potentials 2.2. The Resting Membrane Potential Nature and Magnitude of the Resting Membrane Potential The resting membrane potential is the difference in electrical potential across the cell membrane when the cell is not stimulated or when the cell is in a state of relaxation. The resting membrane potential holds steady unless changes in electrical current alter the potential. By definition, a cell under such conditions would no longer be “resting.” The resting membrane potential exists because of a tiny excess of negative ions inside the cell and an excess of positive ions outside. The excess negative charges inside are electrically attracted to the excess positive charges outside the cell, and vice versa. The excess charges (ions) collect in a thin shell tight against the inner and outer surfaces of the plasma membrane. In the bulk of the intracellular and extracellular fluid the number of positive and negative charges is balanced. Unlike the diagrammatic representation in this figure, the number of positive and negative charges that have to be separated across a membrane to account for the potential is actually an infinitesimal fraction of the total number of charges in the two compartments. 37 2. Membrane Potentials 2.2. The Resting Membrane Potential Nature and Magnitude of the Resting Membrane Potential Of the ions that can flow across the membrane and affect its electrical potential, Na⁺, K⁺, and Cl⁻ are present in the highest concentrations, and the membrane permeability to each is independently determined. Na⁺ and K⁺ generally make the most important contributions in generating the resting membrane potential, but in some cells Cl⁻ is also a factor. The Na⁺ and Cl⁻ concentrations are lower inside the cell than outside, whereas the K⁺ concentration is greater inside the cell. The concentration differences for Na⁺ and K⁺ are established by the action of the sodium/potassium-ATPase pump (Na⁺/K⁺-ATPase) that pumps Na⁺ out of the cell and K⁺ into it. The reason for the Cl⁻ distribution varies between cell types. 38 2. Membrane Potentials 2.2. The Resting Membrane Potential Nature and Magnitude of the Resting Membrane Potential The magnitude of the resting membrane potential depends mainly on two factors: (1) differences in specific ion concentrations in the intracellular and extracellular fluids; (2) differences in membrane permeabilities to the different ions, which reflect the number of open channels for the different ions in the plasma membrane. (3) A third factor, a direct contribution from ion pumps, has a very minor role. Let’s examine each of these. 39 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences To understand how concentration differences for Na⁺ and K⁺ create membrane potentials, first consider what happens when the membrane is permeable (has open channels) to only one ion. In this hypothetical situation, assume that the membrane contains K⁺ channels but no Na⁺ or Cl⁻ channels. Figure (a): ✓ Initially, compartment 1 contains 0.15 M NaCl and compartment 2 contains 0.15 M KCl. ✓ No ion movement occurs because the channels are closed. ✓ There is no potential difference across the membrane because the two compartments contain equal numbers of positive and negative ions. The positive ions are different: Na⁺ versus K⁺, but the total numbers of positive ions in the two compartments are the same, and each positive ion balances a chloride ion. 40 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences Figure (b): ✓ When the K⁺ channels are opened, K⁺ will diffuse down its concentration gradient from compartment 2 into compartment 1 ✓ Sodium ions will not be able to move across the membrane. Figure (c): ✓ After a few potassium ions have moved into compartment 1, that compartment will have an excess of positive charge, leaving behind an excess of negative charge in compartment 2. ✓ Thus, a potential difference has been created across the membrane. This introduces another major factor that can cause net movement of ions across a membrane: an electrical potential. 41 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences Figure (d): ✓ As compartment 1 becomes increasingly positive and compartment 2 increasingly negative, the membrane potential difference begins to influence the movement of the potassium ions. The negative charge of compartment 2 tends to attract them back into their original compartment, and the positive charge of compartment 1 tends to repel them out of compartment 1. ✓ In other words, there is an electrochemical gradient across the membrane for all ions. As long as the flux or movement of ions due to the K⁺ concentration gradient is greater than the flux due to the membrane potential, net flux of K⁺ will occur from compartment 2 to compartment 1 and the membrane potential will progressively increase. 42 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences Figure (e): ✓ The membrane potential will become negative enough to produce a flux equal but opposite to the flux produced by the concentration gradient. The membrane potential at which these two fluxes become equal in magnitude but opposite in direction is called the equilibrium potential for that ion; in this case, K+. At the equilibrium potential for an ion, there is no net movement of the ion because the opposing fluxes are equal, and the potential will undergo no further change. 43 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences As long as a concentration gradient was initially present and there was open channels for K⁺, a membrane potential was automatically generated. The number of ions crossing the membrane to establish this equilibrium potential is insignificant compared to the number originally present in compartment 2, so there is no significant change in the K⁺ concentration in either compartment between step (a) and step (e). 44 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences The magnitude of the equilibrium potential (in mV) for any type of ion depends on the concentration gradient for that ion across the membrane. If the concentrations on the two sides were equal, the net flux would be zero and the equilibrium potential would also be zero. The larger the concentration gradient, the larger the equilibrium potential because a larger, electrically driven movement of ions will be required to balance the movement due to the concentration difference. 45 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences The equilibrium potential for one ion can be different in magnitude and direction from those for other ions, depending on the concentration gradients between the intracellular and extracellular compartments for each ion. The Nernst equation describes the equilibrium potential for any ion, referred to as the electrical potential necessary to balance a given ionic concentration gradient across a membrane so that the net flux of the ion is zero. The Nernst equation is: 46 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Concentration Differences Using the concentration gradients for the following ions, the equilibrium potentials for Na⁺ and K⁺ are: Thus, at these typical concentrations, Na⁺ flux through open channels will tend to bring the membrane potential toward +60 mV, whereas K⁺ flux will bring it toward − 90 mV. If the concentration gradients change, the equilibrium potentials will change. The hypothetical situations presented here are useful for understanding how individual permeating ions like Na⁺ and K⁺ influence membrane potential, but real cells are far more complicated. Many charged molecules contribute to the overall electrical properties of cell membranes. 47 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Different Ion Permeabilities When channels for more than one type of ion are open in the membrane at the same time, the permeabilities and concentration gradients for all the ions must be considered when accounting for the membrane potential. For a given concentration gradient, the greater the membrane permeability to one type of ion, the greater the contribution that ion will make to the membrane potential. Given the concentration gradients and relative membrane permeabilities (P ion) for Na⁺, K⁺, and Cl⁻, the resting membrane potential of a membrane (Vm) can be calculated using the Goldman-Hodgkin-Katz (GHK) equation: The GHK equation is essentially an expanded version of the Nernst equation that takes into account individual ion permeabilities. 48 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Different Ion Permeabilities Note that the Cl⁻ concentrations are reversed as compared to Na⁺ and K⁺, because Cl⁻ is an anion and its movement has the opposite effect on the membrane potential. Ion gradients and permeabilities vary widely in different excitable cells of the human body and in other animals, and yet the GHK equation can be used to determine the resting membrane potential of any cell if the conditions are known. For example, if the relative permeability values of a cell were P(K) = 1, P(Na) = 0.04, and P(Cl) = 0.45, the resting membrane potential would be: The contributions of Na⁺, K⁺, and Cl⁻ to the overall membrane potential are thus a function of their concentration gradients and relative permeabilities. 49 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Different Ion Permeabilities The concentration gradients determine their equilibrium potentials, and the relative permeability determines how strongly the resting membrane potential is influenced toward those potentials. In mammalian neurons, the K⁺ permeability may be as much as 100 times greater than that for Na⁺ and Cl⁻, so neuronal resting membrane potentials are typically fairly close to the equilibrium potential for K⁺. The value of the Cl⁻ equilibrium potential is also near the resting membrane potential in many neurons, but for some reasons, Cl⁻ actually has minimal importance in determining neuronal resting membrane potentials compared to K⁺ and Na⁺. 50 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Different Ion Permeabilities In summary, the resting potential is generated across the plasma membrane largely because of the movement of K⁺ out of the cell down its concentration gradient through open K⁺ channels (called leak channels, or ungated channels). This makes the inside of the cell negative with respect to the outside. Even though K⁺ flux has more impact on the resting membrane potential than does Na⁺ flux, the resting membrane potential is not equal to the K⁺ equilibrium potential, because having a small number of open leak channels for Na⁺ pulls the membrane potential slightly toward the Na⁺ equilibrium potential. Thus, at the resting membrane potential, ion channels allow net movement both of Na⁺ into the cell and K⁺ out of the cell. Over time, the concentrations of intracellular sodium and potassium ions do not change, however, because of the action of the Na⁺/K⁺-ATPase pump. In a resting cell, the number of ions the pump moves equals the number of ions that leak down their electrochemical gradient. As long as the concentration gradients remain stable and the ion permeabilities of the plasma membrane do not change, the electrical potential across the resting membrane will also remain constant. 51 2. Membrane Potentials 2.2. The Resting Membrane Potential Magnitude of the Resting Membrane Potential: Contribution of Ion Pump The leak of Na⁺ and K⁺ down their electrochemical gradients through ion channels is the main factor in determining the resting membrane potential, but the Na⁺/K⁺-ATPase pump is essential to this process because it maintains the concentration gradients. In addition, the pump plays a very minor direct role in creating a negative resting potential because with each cycle it moves three Na⁺ out of the cell for every two K⁺ that it brings in. This unequal transport of positive ions makes the inside of the cell more negative than it would be from ion diffusion alone. When a pump moves net charge across the membrane and contributes directly to the membrane potential, it is known as an electrogenic pump. In most cells, the electrogenic contribution to the membrane potential is quite small. Even though the electrogenic contribution of the Na⁺/K⁺-ATPase pump is small, the pump always makes an essential indirect contribution to the membrane potential because it maintains the concentration gradients that result in ion diffusion and charge separation. 52 2. Membrane Potentials 2.2. The Resting Membrane Potential Summary of the Development of a Resting Membrane Potential When a membrane potential is maintained at a resting value of – 70 mV, the inward and outward leak of positive ions must be equal even though there is a greater permeability to K⁺. How does this steady state develop? This process is summarized in three conceptual steps. First step: ✓ The action of the Na⁺/K⁺-ATPase pump sets up the concentration gradients for Na⁺ and K⁺. These concentration gradients determine the equilibrium potentials for the two ions which is, the value to which each ion would bring the membrane potential if it were the only permeating ion. ✓ Simultaneously, the pump has a small electrogenic effect on An Na+/K+-ATPase pump establishes the membrane due to the fact that three Na⁺ are pumped out for concentration gradients and generates a every two K⁺ pumped in. small negative potential. 53 2. Membrane Potentials 2.2. The Resting Membrane Potential Summary of the Development of a Resting Membrane Potential Second step: ✓ The next step shows that initially there is a greater flux of K⁺ out of the cell than Na⁺ into the cell. This is because in a resting membrane there is a greater permeability (more leak channels) to K⁺ than there is to Na⁺. ✓ Because there is greater net efflux than influx of positive ions during this step, a significant negative membrane potential develops, with the value approaching that of the K⁺ equilibrium potential. Greater net movement of K⁺ than Na⁺ makes the membrane potential more negative on the inside. 54 2. Membrane Potentials 2.2. The Resting Membrane Potential Summary of the Development of a Resting Membrane Potential Third step: ✓ In the steady-state resting neuron, the flux of ions across the membrane reaches a dynamic balance in which K⁺ is highly permeable but has a small electrochemical gradient and Na⁺ has low permeability but a large electrochemical gradient. In this state the inward and outward currents are equal, so the membrane potential rests at a steady value. At a steady negative resting membrane potential, ion fluxes through the channels and pump balance each other. 55 2. Membrane Potentials 2.2. The Resting Membrane Potential Summary of the Development of a Resting Membrane Potential Now let’s return to the behavior of chloride ions in excitable cells. The plasma membranes of many cells also have Cl− channels but do not contain chloride ion pumps. Therefore, in these cells, Cl− concentrations simply shift until the equilibrium potential for Cl− is equal to the resting membrane potential. In other words, the negative membrane potential determined by Na+ and K+ moves Cl− out of the cell, and the Cl− concentration inside the cell becomes lower than that outside. This concentration gradient produces a diffusion of Cl− back into the cell that exactly opposes the movement out because of the electrical potential. In contrast, some cells have a non-electrogenic active transport system that moves Cl− out of the cell, generating a strong concentration gradient. In these cells, the Cl− equilibrium potential is negative to the resting membrane potential, and net Cl− diffusion into the cell contributes to the excess negative charge inside the cell; net Cl− diffusion makes the membrane potential more negative than it would be if only Na+ and K+ were involved. 56