Excitable Tissues Resting Membrane Potential 2024 PDF

Prepared & prepared by Dr. Shimaa Mohammad Yousof Associate prof. of Medical Physiology KAU-Rabigh Branch 2024  Introduction to Excitable Tissues  OBJECTIVES  AT THE END OF THIS LECTURE THE STUDENT SHOULD BE ABLE TO:  Outline the definiti...

Prepared & prepared by Dr. Shimaa Mohammad Yousof Associate prof. of Medical Physiology KAU-Rabigh Branch 2024  Introduction to Excitable Tissues  OBJECTIVES  AT THE END OF THIS LECTURE THE STUDENT SHOULD BE ABLE TO:  Outline the definition and significance of tissue excitability.  Outline the classifications of stimuli according to physical nature, source, and intensity.  Enumerate the types of excitable tissues.  Describe the functional organization and major levels of the nervous system.  Describe the structural and functional classes of neurons.  Enumerate the functions of the nervous system. 9/29/2024 3 WHAT ARE THE EXCITABLE TISSUES? NERVES sensory, motor, mixed MUSCLES skeletal, cardiac, smooth 9/29/2024 4  WHAT IS THE STIMULUS? It is any change in the environment surrounding the living tissue that causes it to react. 9/29/2024 5  WHAT ARE THE TYPES OF STIMULI? A) According to the nature: B) According to the intensity: 1. Electrical 1. Subthreshold 2. Chemical 2. Threshold 3. Mechanical 3. Maximal stimulus 4. Thermal 4. Supramaximal C) According to the Source: 1. Internal 2. External 9/29/2024 6  WHAT ARE THE TYPES OF STIMULI? A) According to the physical nature: 1.Electrical  electricity 2.Chemical  chemical substances 3.Mechanical  blow to the eye 4.Thermal  heat and cold N.B. The electrical stimulation is used in physiology to evoke the response because: 1.it is similar to the normal electrical phenomena 2.its duration and amplitude can be adjusted 9/29/2024 7  WHAT ARE THE TYPES OF STIMULI? B) According to the intensity: 1. Subthreshold: None of the axons are stimulated and no response occurs. 2. Threshold: The minimum stimulus needed to achieve an action potential. Axons with low thresholds fire and a small potential change is observed. 3. Maximal stimulus: The stimulus that produces excitation of all the axons. 4. Supramaximal stimulus: produces no further increase in the size of the observed potential. Threshold = enough intensity + enough duration 9/29/2024 8 General Organization of the NS  ORGANIZATION OF THE NERVOUS SYSTEM The nervous system has two main divisions: 1. The central nervous system (CNS): Is composed of the brain and the spinal cord. This system controls behavior. 2. The peripheral nervous system (PNS): Is composed of peripheral nerves. This system is a pathway to and from internal organs and the CNS. ORGANIZATION OF THE NERVOUS SYSTEM  HISTOLOGICAL ORGANIZATION 1. Neurons: The neuron is the basic structural unit of NS. 2. Glial Cells (neuroglia): Neuroglia (supporting cells) are the matrix of CNS. STRUCTURE OF A “TYPICAL” NEURON  Structural Classes of Neurons - Some of the types of neurons in the mammalian nervous system. A) Unipolar neurons have one process, with different segments serving as receptive surfaces and releasing terminals. B) Bipolar neurons have two specialized processes: a dendrite that carries information to the cell and an axon that transmits information from the cell. C) Some sensory neurons are in a subclass of bipolar cells called pseudounipolar cells. As the cell develops, a single process splits into two, both of which function as axons—one going to skin or muscle and another to the spinal cord.  Structural Classes of Neurons - D) Multipolar cells have one axon and many dendrites. Examples include motor neurons, hippocampal pyramidal cells with dendrites in the apex and base, and cerebellar Purkinje cells with an extensive dendritic tree in a single plane. “Ganong”  STRUCTURE OF THE NEURON It is composed of three major parts: 1- The soma, which is the main body of he neuron; 2-A single axon, which extends from The soma into a peripheral nerve that leaves the spinal cord; 3-The dendrites, which are great numbers of branching projections of the soma. 9/29/2024 16  Functional Classes of Neurons 1- sensory 2- motor 3- mixed 9/29/2024 17  FUNCTIONS OF NERVOUS SYSTEM 1- Sensation of changes both inside to outside the body. 2- Interpretation of these changes. 3- Reaction to changes such as by muscular contraction or glandular secretion. Resting Membrane Potential  OBJECTIVES  AT THE END OF THIS LECTURE THE STUDENT SHOULD BE ABLE TO:  Explain the biophysical and chemical principles underlying membrane potentials.  Explain the biophysical and chemical factors contributing to resting membrane potential.  Calculate the magnitude of resting membrane potentials using Nernst and Goldman’s equations.  Vander: Ch6. Neuronal Signaling and the Structure of the Nervous System. P: 143-148.  Guyton: Ch5: Membrane Potentials and Action Potentials. P: 63-67 9/29/2024 20 - -  ACCEPTED The cell decision Accept both Na+ and K+ in addition to their friend S - NA+K+-ATPase to Work in collaboration with each S other to raise the quality of the cell company. r 9/29/2024 22  Differences Between Extracellular and Intracellular fluids ECF ICF Site of presence Outside the cells in Inside cells the blood vessels and the interstitial spaces between cells. Composition Large amounts of Large amounts of sodium, chloride,potassium, and bicarbonate magnesium, and ions. phosphate ions* negatively charged *Nutrients for the proteins cells, such as oxygen, glucose, fatty acids, and amino acids. * Percentage 1/3 total body water 2/3 total body water 9/29/2024 23  MEMBRANE POTENTIALS Basic Principles of Electricity:  There are differences in the composition of the extracellular and intracellular fluids.  Due to the distribution of these charged ions  the inside of the cell membrane is relatively negative to the outside. 9/29/2024 24  potdiee in the Gest S -70 DISTRIBUTION OF IONS AND CHARGES ACROSS CELL MEMBRANE 9/29/2024 25 By Dr. Ahmad Bamagoos  MEMBRANE POTENTIALS Basic Principles of Electricity Like charges repel each other. *Positive charge repels positive charge, *Negative charge repels negative charge. An electric force draws oppositely charged substances together. 9/29/202  MEMBRANE POTENTIALS Definitions:  Potential difference: “the difference in the amount of charge between two points”.  Current: “The movement of electric charge”.  The current depends on: 1- the potential difference between the charges and 2- the nature of the material through which they are moving. 9/29/2024 28  MEMBRANE POTENTIALS The cell membranes of nerves, like those of other cells, contain many different types of ion channels: (A) LEAK CHANNELS (B) GATED CHANNELS 1- voltage-gated: stimulated by change in the voltage 2- ligand-gated: stimulated by attachment of a substance. Role of membrane channels in membrane potential: It is the behavior of these channels, and particularly Na+ and K+ channels, that explains the electrical events in nerves. 9/29/2024 33 MEMBRANE POTENTIALS 9/29/2024 34 9/29/2024 35  THE DIFFUSION POTENTIAL  “The potential difference across a selectively permeable membrane to one ion, at which the diffusion of this ion in one direction is stopped.”  e.g.  Na+ from outside to inside  K+ from inside to outside 9/29/2024 36  THE NERNST POTENTIAL  “The diffusion potential across a membrane that exactly opposes the net diffusion of a single particular ion through the membrane”. 9/29/2024 37  THE GOLDMAN (GOLDMAN-HODGKINKATZ) EQUATION  Is Used to Calculate the Diffusion Potential When the membrane Is Permeable to Several Different Ions.  When a membrane is permeable to several different ions, the diffusion potential that develops depends on three factors: (1) the polarity of the electrical charge of each ion; (2) the permeability of the membrane (P) to each ion; (3) the concentration (C) of the respective ions on the inside (i) and outside (o) of the membrane. Thus, the formula gives the calculated membrane potential on the inside of the membrane when (Na+), (K+), and (Cl−), are involved. 9/29/2024 38  THE RESTING MEMBRANE POTENTIAL  The resting membrane potential (RMP): “The potential difference across the plasma membranes of the cell during resting state”.  What is the origin (or ionic basis) of RMP???? 1- Selective ion permeability:?? 2- Sodium-potassium pump:?? & 9/29/2024 39 THE RESTING MEMBRANE POTENTIAL 9/29/2024 40  THE RESTING MEMBRANE POTENTIALS 1- Selective ion permeability: (Initiates) K+ permeability at rest is greater than Na+ permeability. K+ moves out of cells and Na+ moves in through leak channels  Therefore, CREATE a POTENTIAL DIFFERENCE OF 70 mv during rest. SO, THE RMP IN THE NERVE CELL IS -70 mV. 9/29/2024 41  THE RESTING MEMBRANE POTENTIALS 2- Na+-K+ ATPase pump: * Provide an additional contribution to the RMP (MAINTAINS). There is continuous pumping of - 3 Na+ ions to the outside for each - 2 K+ ions pumped to the inside of the membrane. 9/29/2024 42  THE RESTING MEMBRANE POTENTIALS * 2- Na+-K+ ATPase pump: The fact that more sodium ions are being pumped to the outside than potassium to the inside causes continual loss of positive charges from inside the membrane; this creates an additional degree of negativity on the inside beyond that which can be accounted for by diffusion 9/29/2024 43 alone.  THE MEMBRANE POTENTIALS Establishment of resting membrane potentials under three conditions. A,When the membrane potential is caused entirely by potassium diffusion alone. B, When the membrane potential is caused by diffusion of both sodium and potassium ions. C, When the membrane potential is caused by diffusion of both sodium and potassium ions plus pumping of both these ions by the Na+-K+ pump. 9/29/2024 44  MEMBRANE POTENTIALS Special Terms Related to Membrane Polarity Depolarization, Repolarization, Hyperpolarization  Depolarization: occurs due to decreased negativity inside the cell in response to a stimulus or spontaneously  i.e. the potential difference is more near to the firing level of the cell.  Repolarization: occurs due to the process of regaining the membrane potential toward the resting membrane potential.  Hyperpolarization: occurs due to increased negativity inside the cell below the resting membrane potential  i.e. the membrane potential is more far away from the firing level  tissue is less excitable. 9/29/2024 47  MEMBRANE POTENTIALS Special Terms Related to Membrane Polarity Depolarization, Repolarization, Hyperpolarization By Dr. Ahmad Bamagoos  EFFECTS OF IONIC DISTURBANCES ON MEMBRAN POTENTIAL  Hypernatremia  Hyperexcitability.  Hyponatremia  reduces the size of the action potential but has little effect on the RMP.WHY?  because the permeability of the membrane to Na+ at rest is relatively low.  In contrast, since the resting membrane potential is close to the equilibrium potential for K+  changes in the external concentration of K+ can have major effects on RMP.  Hyperkalemia  the RMP moves closer to the threshold (less negative) for eliciting an action potential and the neuron becomes more excitable  Hyperexcitability.  Hypokalemia  the membrane potential is reduced (more negative) and the neuron is hyperpolarized  Hypoexcitability.  EFFECTS OF IONIC DISTURBANCES ON MEMBRAN POTENTIAL  Hypocalcemia Causes Nervous System Excitement and Tetany. When the ECF concentration of Ca++ falls below normal  the nervous system becomes progressively more excitable?? Ca prevents Na entry to the cell  when decreased  Na enters easily  because of increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials  Hyperexcitabilty.  Hypercalcemia Depresses Nervous System and Muscle Activity.  When Ca++ concentration in the body fluids rises above normal, the nervous system becomes depressed and reflex activities of the central nervous system are sluggish. Hypernatremia, Hyperkalemia,  Hyperexcitability. Hypocalcemia References & Videos:  Ganong W. F., EVIEW OF MEDICAL PHYSIOLOGY, Lange Medical Books/McGraw-Hill Medical Publishing Division , 26th Edition, 2019.  Guyton A. C. & Hall J. E., TEXTBOOK OF MEDICAL PHYSIOLOGY, Elsevier Inc., 14th edition, 2021.  Vander et al., VANDER HUMAN PHYSIOLOGY: THE MECHANISM OF BODY FUNCTION, McGraw-Hill Companies, 16th Edition, 2023.  Videos:  Nernest equation  https://www.youtube.com/watch?v=ZVUWyDzmApg  Diffusion Potential, Equilibrium potential, Nernest and Goldman equations  https://www.youtube.com/watch?v=E14hzilwOsc  Resting Membrane Potential, Ionic basis  https://www.youtube.com/watch?v=vYcAHameIGw 9/29/2024 51  CHAPTER 5 Membrane Potentials and UNIT II Action Potentials Electrical potentials exist across the membranes of virtu- creates a membrane potential of opposite polarity to that ally all cells of the body. Some cells, such as nerve and in Figure 5-1A, with negativity outside and positivity - muscle cells, generate rapidly changing electrochemical inside. Again, the membrane potential rises high enough impulses at their membranes, and these impulses are used within milliseconds to block further net diffusion of to transmit signals along the nerve or muscle membranes. sodium ions to the inside; however, this time, in the mam- In other types of cells, such as glandular cells, macro- malian nerve fiber, the potential is about 61 millivolts posi- phages, and ciliated cells, local changes in membrane tive inside the fiber. potentials also activate many of the cell’s functions. This Thus, in both parts of Figure 5-1, we see that a con- chapter reviews the basic mechanisms whereby mem- centration difference of ions across a selectively perme- Suitabl brane potentials are generated at rest and during action able membrane can, under appropriate conditions, create by nerve and muscle cells. See Video 5-1. a membrane potential. Later in this chapter, we show that many of the rapid changes in membrane potentials observed during nerve and muscle impulse transmission BASIC PHYSICS OF MEMBRANE result from such rapidly changing diffusion potentials. POTENTIALS The Nernst Equation Describes the Relationship of Membrane Potentials Caused by Ion Diffusion Potential to the Ion Concentration Difference Concentration Differences Across a Across a Membrane. The diffusion potential across a Selectively Permeable Membrane membrane that exactly opposes the net diffusion of a par- k+ If In Figure 5-1A, the potassium concentration is great ticular ion through the membrane is called the Nernst po- inside a nerve fiber membrane but very low outside the tential for that ion, a term that was introduced in Chapter See eme membrane. Let us assume that me the membrane in this case 4. The magnitude of the Nernst potential is determined ↑ K + is permeable to the potassium ions but not to any other - - - by the ratio of the concentrations of that specific ion on out ions. Because of the large potassium concentration gradi- the two sides of the membrane. The greater this ratio, the - "The rent - ent - from the inside - - toward the outside, there is a strong greater the tendency for the ion to diffuse in one direction tendency for potassium ions to diffuse outward through and therefore the greater the Nernst potential required to the membrane. As they do so, they carry positive electri- prevent additional net diffusion. The following equation, cal charges to the outside, thus creating electropositivity called the Nernst equation, can be used to calculate the outside the membrane and electronegativity inside the Nernst potential for any univalent ion at the normal body -f membrane because of negative anions that remain behind temperature of 98.6°F (37°C): k+ and do not diffuse outward with the potassium. Within 61 Concentration inside : about 1 millisecond, the potential difference between the EMF (millivolts ) = ± × log z Concentration outside Thigh e inside and outside,> - called the diffusion potential, becomes great enough to block further net potassium diffusion to where EMF is the electromotive force and z is the electri- os the exterior, despite the high potassium ion concentra- cal charge of the ion (e.g., +1 for K+). When using this formula, it is usually assumed that potentialtion gradient. In the normal mammalian nerve fiber, the - potential difference is about 94 millivolts, with negativity the potential in the extracellular fluid outside the mem- inside the fiber membrane. brane remains at zero potential, and the Nernst potential Figure 5-1B shows the same phenomenon as in Fig- is the potential inside the membrane. Also, the sign of the ure 5-1A, but this time with a high concentration of potential is positive (+) if the ion diffusing from inside to sodium ions outside the membrane and a low concentra- outside is a negative ion, and it is negative (−) if the ion is tion of sodium ions inside. These ions are also positively positive. Thus, when the concentration of positive potas- charged. This time, the membrane is highly permeable to sium ions on the inside is 10 times that on the outside, the the sodium ions but is impermeable to all other ions. Dif- log of 10 is 1, so the Nernst potential calculates to be −61 fusion of the positively charged sodium ions to the inside millivolts inside the membrane.␣ 63 UNIT II Membrane Physiology, Nerve, and Muscle DIFFUSION POTENTIALS Table 5-1 Resting Membrane Potential in Different (Anions)– Nerve fiber (Anions)– Nerve fiber Cell Types + – – – + – + – + – (Anions) – + (Anions) + Cell Type Resting Potential (mV) + – – + – + – – + – + + – Neurons −60 to −70 + + – + – + + – + + + – K K Na – + Na Skeletal muscle −85 to −95 + – – + + – + – – + – + + – Smooth muscle −50 to −60 + – – + – + + – (–94 mV) – + (+61 mV) + – Cardiac muscle −80 to −90 + – – + – + + – Hair (cochlea) −15 to −40 + – – + – + + – Astrocyte −80 to −90 A B Erythrocyte −8 to −12 Figure 5-1 A, Establishment of a diffusion potential across a nerve fiber membrane, caused by diffusion of potassium ions from inside Photoreceptor −40 (dark) to −70 (light) the cell to outside the cell through a membrane that is selectively per- meable only to potassium. B, Establishment of a diffusion potential when the nerve fiber membrane is permeable only to sodium ions. inside the membrane. The reason for this phenomenon Note that the internal membrane potential is negative when potas- sium ions diffuse and positive when sodium ions diffuse because of is that excess positive ions diffuse to the outside when opposite concentration gradients of these two ions. their concentration is higher inside than outside the membrane. This diffusion carries positive charges to the outside but leaves the nondiffusible negative anions on the inside, thus creating electronegativity on the inside. The Goldman Equation Is Used to Calculate the Dif- The opposite effect occurs when there is a gradient for fusion Potential When the Membrane Is Permeable a negative ion. That is, a chloride ion gradient from the to Several Different Ions. When a membrane is per- outside to the inside causes negativity inside the cell meable to several different ions, the diffusion potential because excess negatively charged chloride ions diffuse that develops depends on three factors: (1) the polarity to the inside while leaving the nondiffusible positive ions of the electrical charge of each ion; (2) the permeability on the outside. of the membrane (P) to each ion; and (3) the concentra- Fourth, as explained later, the permeability of the tion (C) of the respective ions on the inside (i) and out- sodium and potassium channels undergoes rapid side (o) of the membrane. Thus, the following formula, changes during transmission of a nerve impulse, called the Goldman equation or the Goldman-Hodgkin- whereas the permeability of the chloride channels does Katz equation, gives the calculated membrane potential not change greatly during this process. Therefore, rapid on the inside of the membrane when two univalent pos- changes in sodium and potassium permeability are pri- itive ions, sodium (Na+) and potassium (K+), and one marily responsible for signal transmission in neurons, univalent negative ion, chloride (Cl−), are involved: which is the subject of most of the remainder of this CNa+ PNa+ + CK+ PK+ + CCIo− PCI− chapter.␣ EMF (millivolts ) = −61 × log i i CNao+ PNa+ + CKo+ PK+ + CCIi− PCI− Resting Membrane Potential of Different Cell Types. In Several key points become evident from the Goldman some cells, such as the cardiac pacemaker cells discussed in Chapter 10, the membrane potential is continuously equation. First, sodium, potassium, and chloride ions are changing, and the cells are never “resting”. In many other the most important ions involved in the development of cells, even excitable cells, there is a quiescent period in which membrane potentials in nerve and muscle fibers, as well a resting membrane potential can be measured. Table 5-1 as in the neuronal cells. The concentration gradient of shows the approximate resting membrane potentials of some each of these ions across the membrane helps determine different types of cells. The membrane potential is obviously the voltage of the membrane potential. very dynamic in excitable cells such as neurons, in which Second, the quantitative importance of each of the ions action potentials occur. However, even in nonexcitable cells, in determining the voltage is proportional to the membrane the membrane potential (voltage) also changes in response permeability for that particular ion. If the membrane has to various stimuli, which alter activities for the various ion zero permeability to sodium and chloride ions, the mem- transporters, ion channels, and membrane permeability for brane potential becomes entirely dominated by the concen- sodium, potassium, calcium, and chloride ions. The resting membrane potential is, therefore, only a brief transient state tration gradient of potassium ions alone, and the resulting for many cells.␣ potential will be equal to the Nernst potential for potassium. Electrochemical Driving Force. When multiple ions The same holds true for each of the other two ions if the contribute to the membrane potential, the equilibrium membrane should become selectively permeable for either potential for any of the contributing ions will differ from one of them alone. the membrane potential, and there will be an electrochemi- Third, a positive ion concentration gradient from inside cal driving force (Vdf) for each ion that tends to cause net the membrane to the outside causes electronegativity 64  Chapter 5 Membrane Potentials and Action Potentials 0 Nerve fiber –+–+–+–+–+–+–+– — + +–++––+–+––++–+ –+–+–+–+–+–+–+– +–++––+–+––++–+ –+–+–+–+–+–+–+– I +–++––+–+––++–+ KC Silver–silver –+–+–+–+–+–+–+– UNIT II +++++++++++ +++++ chloride +–++––+–+––++–+ –––––––––– ––––– electrode –+–+–+–+–+–+–+– +–++––+–+––++–+ Electrical potential – – – – – – – – – (–70 – – – – – – – 0 + + + + + + + + + mV) + + + + + + + + (millivolts) Figure 5-2 Measurement of the membrane potential of the nerve fiber using a microelectrode. –70 movement of the ion across the membrane. This driving force is equal to the difference between the membrane po- Figure 5-3 Distribution of positively and negatively charged ions in tential (Vm) and the equilibrium potential of the ion (Veq) the extracellular fluid surrounding a nerve fiber and in the fluid inside the fiber. Note the alignment of negative charges along the inside Thus, Vdf = Vm – Veq. surface of the membrane and positive charges along the outside The arithmetic sign of Vdf (positive or negative) and the surface. The lower panel displays the abrupt changes in membrane valence of the ion (cation or anion) can be used to predict potential that occur at the membranes on the two sides of the fiber. the direction of ion flow across the membrane, into or out of the cell. For cations such as Na+ and K+, a positive Vdf predicts ion movement out of the cell down its electro- is zero, which is the potential of the extracellular fluid. chemical gradient, and a negative Vdf predicts ion move- Then, as the recording electrode passes through the volt- ment into the cell. For anions, such as Cl−, a positive Vdf age change area at the cell membrane (called the electrical predicts ion movement into the cell, and a negative Vdf pre- dipole layer), the potential decreases abruptly to −70 mil- dicts ion movement out of the cell. When Vm = Veq, there livolts. Moving across the center of the fiber, the potential is no net movement of the ion into or out of the cell. Also, remains at a steady −70-millivolt level but reverses back the direction of ion flux through the membrane reverses as to zero the instant it passes through the membrane on the Vm becomes greater than or less than Veq; hence, the equi- opposite side of the fiber. librium potential (Veq) is also called the reversal potential.␣ To create a negative potential inside the membrane, only enough positive ions to develop the electrical dipole layer at the membrane itself must be trans- Measuring the Membrane Potential ported outward. The remaining ions inside the nerve The method for measuring the membrane potential is fiber can be both positive and negative, as shown in simple in theory but often difficult in practice because of the upper panel of Figure 5-3. Therefore, transfer of the small size of most of the cells and fibers. Figure 5-2 an incredibly small number of ions through the mem- shows a small micropipette filled with an electrolyte solu- brane can establish the normal resting potential of −70 tion. The micropipette is impaled through the cell mem- millivolts inside the nerve fiber, which means that only brane to the interior of the fiber. Another electrode, called about 1/3,000,000 to 1/100,000,000 of the total posi- the indifferent electrode, is then placed in the extracellu- tive charges inside the fiber must be transferred. Also, lar fluid, and the potential difference between the inside an equally small number of positive ions moving from and outside of the fiber is measured using an appropriate outside to inside the fiber can reverse the potential voltmeter. This voltmeter is a highly sophisticated elec- from −70 millivolts to as much as +35 millivolts within tronic apparatus that is capable of measuring small volt- as little as 1/10,000 of a second. Rapid shifting of ions in ages despite extremely high resistance to electrical flow this manner causes the nerve signals discussed in sub- through the tip of the micropipette, which has a lumen sequent sections of this chapter.␣ diameter usually less than 1 micrometer and a resistance of more than 1 million ohms. For recording rapid changes RESTING MEMBRANE POTENTIAL OF in the membrane potential during transmission of nerve NEURONS impulses, the microelectrode is connected to an oscillo- scope, as explained later in the chapter. The resting membrane potential of large nerve fibers when The lower part of Figure 5-3 shows the electrical they are not transmitting nerve signals is about −70 mil- potential that is measured at each point in or near the livolts. That is, the potential inside the fiber is 70 millivolts nerve fiber membrane, beginning at the left side of the more negative than the potential in the extracellular fluid figure and passing to the right. As long as the electrode is on the outside of the fiber. In the next few paragraphs, the outside the neuronal membrane, the recorded potential transport properties of the resting nerve membrane for 65 UNIT II Membrane Physiology, Nerve, and Muscle Outside K+ 3Na+ 2K+ Selectivity K+ 4 mEq/L filter K+ 140 mEq/L (–94 mV) (–94 mV) A 3Na+ Na+ K+ Na+ K+ ATP ADP 2K+ K+ "leak" 142 mEq/L 4 mEq/L Na+-K+ pump channels Figure 5-4 Functional characteristics of the Na+-K+ pump and the K+ Na+ K+ “leak” channels. The K+ leak channels also leak Na+ ions into the cell 14 mEq/L 140 mEq/L (–86 mV) slightly but are much more permeable to K+. ADP, Adenosine diphos- (+61 mV) (–94 mV) phate; ATP, adenosine triphosphate. B sodium and potassium and the factors that determine the + – – + level of this resting potential are explained. + – – + Diffusion – + Active Transport of Sodium and Potassium Ions + – – + Through the Membrane—the Sodium-Potassium Na+ Na+ – + pump (Na+-K+) Pump. Recall from Chapter 4 that all cell mem- + – – + branes of the body have a powerful Na+-K+ pump that 142 mEq/L + – 14 mEq/L – + continually transports sodium ions to the outside of the + – – + + – – + cell and potassium ions to the inside, as illustrated on the – + left side in Figure 5-4. Note that this is an electrogenic Diffusion – + pump because three Na+ ions are pumped to the outside + – – + K+ K+ for each two K+ ions to the inside, leaving a net deficit of pump – + + – – + positive ions on the inside and causing a negative poten- 4 mEq/L + – 140 mEq/L – + tial inside the cell membrane. + – – + The Na+-K+ pump also causes large concentration gra- + – (–90 mV) – + dients for sodium and potassium across the resting nerve + – – + (Anions)– + – (Anions)– membrane. These gradients are as follows: C – + Na+ (outside): 142 mEq/L Figure 5-5 Establishment of resting membrane potentials under three conditions. A, When the membrane potential is caused entirely by potassium diffusion alone. B, When the membrane potential is Na+ (inside): 14 mEq/L caused by diffusion of both sodium and potassium ions. C, When the membrane potential is caused by diffusion of both sodium and potassium ions plus pumping of both these ions by the Na+-K+ pump. K + (outside): 4 mEq/L channels may also leak sodium ions slightly but are far K + (inside): 140 mEq/L more permeable to potassium than to sodium, normally The ratios of these two respective ions from the inside about 100 times as permeable. As discussed later, this dif- to the outside are as follows: ferential in permeability is a key factor in determining the level of the normal resting membrane potential.␣ Na+ inside /Na+ outside = 0.1 Origin of the Normal Resting Membrane Potential K + inside /K + outside = 35.0 Figure 5-5 shows the important factors in the establish- ␣ ment of the normal resting membrane potential. They are Leakage of Potassium Through the Nerve Cell Mem- as follows. brane. The right side of Figure 5-4 shows a channel pro- tein (sometimes called a tandem pore domain, potassium Contribution of the Potassium Diffusion Potential. channel, or potassium [K+] “leak” channel) in the nerve In Figure 5-5A, we assume that the only movement of membrane through which potassium ions can leak, even ions through the membrane is diffusion of potassium in a resting cell. The basic structure of potassium channels ions, as demonstrated by the open channels between was described in Chapter 4 (Figure 4-4). These K+ leak the potassium symbol (K+) inside and outside the mem- 66  Chapter 5 Membrane Potentials and Action Potentials brane. Because of the high ratio of potassium ions inside 0 to outside, 35:1, the Nernst potential corresponding to this ratio is −94 millivolts because the logarithm of 35 is — + 1.54, and this, multiplied by −61 millivolts, is −94 mil- livolts. Therefore, if potassium ions were the only factor I KC Silver–silver causing the resting potential, the resting potential inside chloride UNIT II the fiber would be equal to −94 millivolts, as shown in ++++ –––– +++++ electrode –––– ++++ ––––– the figure.␣ –––– ++++ –––––– Contribution of Sodium Diffusion Through the ++++ –––– ++++++ Nerve Membrane. Figure 5-5B shows the addition of slight permeability of the nerve membrane to sodium ions, caused by the minute diffusion of sodium ions Overshoot through the K+-Na+ leak channels. The ratio of sodium +35 ions from inside to outside the membrane is 0.1, which gives a calculated Nernst potential for the inside of the 0 membrane of +61 millivolts. Also shown in Figure 5-5B Millivolts tion Re p is the Nernst potential for potassium diffusion of −94 olariza olar millivolts. How do these interact with each other, and iza what will be the summated potential? This question can Dep tio n be answered by using the Goldman equation described –70 previously. Intuitively, one can see that if the membrane Resting is highly permeable to potassium but only slightly per- meable to sodium, the diffusion of potassium contributes 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 far more to the membrane potential than the diffusion of Milliseconds sodium. In the normal nerve fiber, the permeability of Figure 5-6 Typical action potential recorded by the method shown the membrane to potassium is about 100 times as great in the upper panel. as its permeability to sodium. Using this value in the Goldman equation, and considering only sodium and varies in different cells from as low as around −10 mil- potassium, gives a potential inside the membrane of −86 - livolts in erythrocytes to as high as −90 millivolts in skel- millivolts, which is near the potassium potential shown etal muscle cells.␣ in the figure.␣ - - - a NEURON ACTION POTENTIAL Contribution of the Na+-K+ Pump. In Figure 5-5C, the Na+-K+ pump is shown to provide an additional contribu- Nerve signals are transmitted by action potentials, which tion to the resting potential. This figure shows that con- are rapid changes in the membrane potential that spread tinuous pumping of three sodium ions to the outside oc- rapidly along the nerve fiber membrane. Each action poten- curs for each two potassium ions pumped to the inside of tial begins with a sudden change from the normal resting the membrane. The pumping of more sodium ions to the negative membrane potential to a positive potential and outside than the potassium ions being pumped to the in- ends with an almost equally rapid change back to the nega- side causes a continual loss of positive charges from inside tive potential. To conduct a nerve signal, the action potential the membrane, creating an additional degree of negativity moves along the nerve fiber until it comes to the fiber’s end. (about −4 millivolts additional) on the inside, beyond that The upper panel of Figure 5-6 shows the changes which can be accounted for by diffusion alone. that occur at the membrane during the action potential, Therefore, as shown in Figure 5-5C, the net mem- with the transfer of positive charges to the interior of the brane potential when all these factors are operative at the fiber at its onset and the return of positive charges to the same time is about −90 millivolts. However, additional exterior at its end. The lower panel shows graphically the ions, such as chloride, must also be considered in calcu- successive changes in membrane potential over a few lating the membrane potential. 10,000ths of a second, illustrating the explosive onset of In summary, the diffusion potentials alone caused the action potential and the almost equally rapid recovery. by potassium and sodium diffusion would give a mem- The successive stages of the action potential are as follows. brane potential of about −86 millivolts, with almost all of this being determined by potassium diffusion. An addi- - Resting Stage. The resting stage is the resting membrane tional −4 millivolts is then contributed to the membrane potential before the action potential begins. The mem- potential by the continuously acting electrogenic Na+- brane is said to be “polarized” during this stage because K+ pump, and there is a contribution of chloride ions. As of the −70 millivolts negative membrane potential that is mentioned previously, the resting membrane potential present.␣ 67