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LECTURE ON THE PHYSIOLOGY OF MEMBRANE EXCITABILITY: RESTING MEMBRANE POTENTIALS, ACTION POTENTIALS (Pre-Lecture Handout and Guide Questions on Electrophysiology I, Cell Module, June 24. 2003) Lecturer: Dante G. Simbulan, Jr., Ph.D., Department of Physiology

(To be included in 2nd Evaluation exams scheduled on June 27)

(Keep this handout. This is your entry point to molecular neuroscience (as part of cell module), and will form an important foundation for your forthcoming Neurosciences Module in the second semester. This is both a reviewer handout and a questionnaire for further study, as some portions are left unanswered for you to answer by reading your books. This is a summary of the lecture and notes compiled from various sources. Important references from your textbooks are the following: 1. Ganong, Forces acting on ions, Genesis of the action potential, Transport Across Cell Membranes, esp. subsection on Distribution of ions and other substances across cell membranes, Membrane permeability and Membrane transport proteins, Ion channels, Na+-K+ ATPase , Chapter 1; Excitation and Conduction, Ionic Basis of Excitation and Conduction in Excitable Tissue: Nerve , Chapter 2;sections on skeletal muscle especially Electrical phenomena and Ionic fluxes, sections on cardiac muscle, such as Electrical properties, sections on smooth muscle, in Visceral smooth muscle: electrical properties, all in Excitable Tissue: Muscle, Chapter 3. 2. Guyton, Chapter 5, Membrane Potentials and Action Potentials

3.

*** Medical Physiology,( Walter F. Boron and Emile L. Boulpaep) Chapter 6: Electrophysiology of the Cell Membrane, pp. 145171. and Chapter 7: Electrical Excitability and Action Potentials, pp. 172- 203. Read your books and notes again. This handout is not a substitute for your textbooks but will be very useful in providing a summary.

I. I. II.

III. IV. V. VI. VII. VIII. I.

Ion Currents What are the Factors that cause ions to move across the cell membrane? What are Membrane Potentials ? a. Definition of terms b. Nernst Equation c. Membrane potentials caused by movement of multiple ions d. Role of metabolism in maintaining resting membrane potential e. Estimation of membrane potential: Goldman equation What is the Na+-K+ Pump What are Ion Channels ? What is the Nerve Action Potential ? What are the passive properties of the cell membrane How is an action potential propagated ? How and where is an action potential initiated, and what causes a repetitive discharge of action potentials ? What are Ion Currents ? a. Ion currents are responsible for the creation of electrical events or voltages in biologic systems. b. When recording electrical events from the body, an accumulation of cations attracts electrons from one recording electrode while a simultaneous accumulation of anions repels electrons from the other electrode. c. When stimulating the body with an electric current, electrons at the negative electrode (the cathode) attract positive ions and repel negative ions. The opposite occurs at the positivecharged electrode (the anode). d. Because water molecules are polarized and therefore are attracted to ions, ions move through solutions surrounded by a cloud or shell of water. The size of the shell of hydration around the ion varies depending on the electron properties of the ion. What are the Factors that cause ions to move across the cell membrane? a. Voltage gradients ions are attracted by opposite charges and repelled by like charges b. Chemical or concentration gradients ions move from regions of greater concentration to regions of lesser concentration. c. Metabolic pumping the expenditure of metabolic energy (high-energy phosphate) usually against voltage or chemical gradients is known as metabolic pumping, e.,g. Na+-K+ pump. What are Membrane Potentials ? a. Definition of terms related to membrane potentials: i. The resting membrane potential is the electrical potential (voltage) across the plasma membrane of nonactivated cells, varying from 40 to 90 mV for most nerve, muscle, and glial cells. ii. Polarization is caused by the separation of charges along the cell membrane.

II.

III.

v. Important Note: everywhere except adjacent to the inner and outer surfaces of the
cell membrane itself, the negative and positive charges are exactly equal. vi. vii. Depolarization means the cell is less negative or more positive on the inside than the outside.

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viii. Hyperpolarization means the cell is more negative on the inside than the outside, compared to the original resting membrane potential. ix. Repolarization usually means return to the original potential after a depolarization. b. Nernst Equation i. The Nernst equation (for the equilibrium potential) determines the theoretic membrane potential produced by the diffusion of a single type of ion through a cell membrane. ii. This equation describes the voltage produced when the electrical gradient is equal but opposite to the chemical gradient (i.e., an equilibrium of electrical and chemical forces). iii. An ion will move passively in or out of a cell permeable to that ion until the membrane potential is equal to the Nernst potential. iv. The membrane potential is usually expressed as the millivolts (mV) on the inside compared with the outside. v. This equation contains a constant that may vary slightly from 58 to 61.5 (or 58 to 61.5) when the temperature varies from 25 to 37 C. vi. The Nernst potential is important for the understanding of the membrane potentials, but it usually does not represent the actual nerve membrane potential because more than one ion is able to move through the cell membrane, each with its own Nernst potential. For example, the ENa and EK may be equal to +60 mV and 95 mV, respectively, but the resting membrane potential of the cell might be 85 mV. Nernst Equation, with the constant 61.5 ( = RT/F x 2.3) was derived at 37 centigrade; natural logarithm was converted to logarithm to the base 10, thus the conversion factor 2.3 computed into RT/F x 2.3 = 61.5 the final value . The final, simplified equation at 37 C.

61.5 Eion = Z X log

[ion]ECF [ion]ICF

Since the valence, z, is included here, the ratio of ECF ion concentration : ICF ion concentration is used rather than the reverse.

c. Membrane potentials caused by movement of multiple ions; Goldman Equation i. Genesis of the Resting Membrane Potential (Steady State Potential) 1. The resting membrane potential of a cell represents a steady state, not an equilibrium, because external energy from metabolism is needed to maintain the potential consant. 2. Each ion moves according to its chemical and electrical gradient. 3. In most cells Na+ leaks in and K+ leaks out down their respective electrochemical gradients. 4. The cell membrane at rest is more permeable to K+ than to Na+, such that K+ can leak out more readily than Na+ can leak in. (Its because there are more leaky K+ channels than Na+ leaky channels.)Fig. 4.2A 5. This results in the cell having a net loss of positive charges resulting in the development of a net negative potential on the inside compared with the outside. Fig. 4.2B 6. The inside negativity will reduce the rate at which K+ leaves and increase the rate at which Na+ enters; that is, K+ movement is caused by its chemical gradient and is attenuated by the inside negativity. 7. The resting membrane potential is the membrane potential at which the steady state is reached when the rate of K+ leaving is equal to the rate of Na+ entering. Fig. 4.1 C. ii. Role of metabolism in maintaining the resting membrane potential 1. Na+ continues to leak inward and K+ continues to leak outward, which, if not compensated for, would result in a loss of the chemical gradients for Na+ and K+ to move and a decrease of the membrane potential. 2. Metabolic energy is needed to actively transport, or pump. Na+ out and K+ in to maintain their concentration gradients. iii. Estimation of membrane potential using the Goldman-Hodgkin-Katz equation 1. The Goldman-Hodgkin-Katz equation can be used to estimate a membrane potential provided that the extra- and intracellular concentrations and the membrane permeabilitys of K+, Na+, and Cl- ions are known. Below is the simplified (RT/F constants xPk [K+]ECF + PNa[Na+]ECF + PC)[Cl-]ICF 2.3 already computed at 37 Cl equation:

Pk [K+]ICF + PNa[Na+]ICF + PCl[Cl-]ECF

Vm =

61.5 x log
At 37 C.

2. The ratio of the permeabilities of K+: Na+: Cl- = 1: 0.04: 0.45 where P K= 1, P Na = 0.04 and P Cl- = 0.45 . 3. Note: the ion with a higher permeability (K+) will have a greater effect on the membrane potential than an ion that is less permeable (such as Na+). What is the effect of hypokalemia (low plasma K+ concentration) on cellular excitability of muscles and nerves ? IV. What is the Na+-K+ Pump ? a. It maintains the intracellular Na+ and K+ concentrations. b. Uses ATP c. Transports 3 Na+ for 2 K+ ions, splitting ATP into ADP as the resulting phosphorylation reaction drives the pump. d. It is electrogenic, as it creates a small net outward cation (positive Na+) current, which contributes only a few millivolts to the membrane potential (making the inner surface of the membrane negative at 40 to 90 mV, or an average of 70 mV). e. Cellular metabolism is directly responsible for the maintenance of the resting membrane potential over a long term as it drives the Na+-K+ pump; on the short term, the effects of the Na+-K+ pump are negligible because the intracellular ion concentrations change slowly. f. It is indirectly responsible for the movements of other ions, such as: (a) Ca++ ; (b) sodiumdependent secondary transport (co-transport/ symport systems) of sugars, amino acids and others. g. It is important for control of cell volume by a net outward ionic movement (Na+ principally), which is followed by water molecules . [ Prevents rupture of the cell]. h. Its pump rate depends on the intracellular concentration of sodium , as a result of increased neuronal activity and depolarizations (with inward Na+ movement) making the pump rate higher to pump out sodium while taking in potassium at a ratio of 3 Na+ out :2 K+ in. What are Ion Channels ? a. Characteristics of Ion Channels i. Provide tunnels for ions to move passively through the cell . ii. They are transmembrane complex proteins inserted into the phospholipid bilayer of the membrane. iii. They are specific for certain types of ions, adding to the selective permeability of the membrane. iv. The total current (ion traffic) for along ion channels depends on: 1. Channel conductivity ability to allow an ion to pass 2. Opening probability the number of channels open at any time v. Electrochemical gradient - chemical and electrical driving forces on the ion b. Types of Ion Channels i. Non-gated Channels also known as leaky, or resting ion channels, which remain open most of the time. [ Many common ion channels (Na+, K+, Cl-) are also non-gated. See below for further descriptions.] ii. Gated Channels: 1. All gated ion channels can assume at least two states : (a) open (allowing ions to pass); and (b) closed states (preventing ions to pass), in less than 1 msec, under various conditions. Gating factors can change protein structures of the ion channels to assume the open or closed states. 2. Gating conditions: (a) special receptor/ion channel-ligand binding ; see chemicalgated channels below (b) changes in membrane potential (voltage changes); see voltage-gated channels below, or (b) even mechanical pressure can influence the open or closed states of ion channels, depending on their location and type of cell. This will be covered in sensory physiology in the neurosciences module. 3. Refractory state: some gated ion channels can assume a third state, that of being inactivated. This occurs when depolarization happens for a variable length of time, which closes the channel. 4. Further descriptions on Voltage-gated ion channels, more on this in action potentials, synaptic transmission and the forthcoming Neurosciences module:

V.

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a. At specific range of membrane potential changes, the ion channel gate opens or closes. b. There is a voltage sensor, as well as an ion selectivity filter which determines the specific ion to pass through at particular voltage conditions of the cell membrane. c. Usually has a third state, in addition to the open and closed state , => an inactivated or refractory state: when the membrane potential is maintained at a specific range for a longer time, inactivation occurs, and recovery from this refractory, inactivated state is voltage- and timedependent. Classic example is in the role of these channels in the genesis and termination of the action potential. 5. Further description on chemically-gated or ligand-sensitive ion channels (more on this in synaptic transmission, as well as in the forthcoming neurosciences module): These ion channels open or close when they bind to specific chemicals or specific neurotransmitters a. at either intracellular sites (G-protein coupled receptor-ligand binding; mediated by metabotropic receptors) or to b. extracellular sites (in the case of transmitter binding to directly gated ion channels and these channels are also called ionotropic receptors). iii. Common Ion Channels (both non-gated and gated ion channels are involved here): Of all the common ion channels, three of them are for cations (Na+, K+, Ca++), and there is only one anion-selective ion channel, for chloride ions. : 1. Sodium channels: a. When briefly depolarized, they open, allowing Na+ ions to enter the cell. b. During prolonged depolarization, the channels inactivate, and prevent further Na+ influx. c. Recovery from inactivation requires repolarization (restoration to resting membrane potential contributed by closure of Na+ channels, Na+-K+ pump , and K+ efflux) which takes a few milliseconds at the resting potential. d. At the resting membane potential, approximately half of the voltagesensitive Na+ channels are inactivated. Prolonged depolarizations increase the percentage of channels inactivated. e. Note that there are also leaky Na+ ion channels which are always open. 2. Potassium channels: a. They play an important role in the genesis of the resting membrane potential, in restoring the resting membrane potential through repolarization after Na+-dependent depolarization, and also in inhibitory synapses in the central nervous system. b. There are several types of K+ channels found in nerve, muscle and glial cells; over 40 types described in mammals. ( Nice to know A general classification of these channels: i. Depolarization-activated, noninactivating K+ channels (voltagesensitive). ii. Depolarization-activated, inactivating K+ channel (voltagesensitive) iii. Depolarization- and Ca++-activated K+ channel (voltage-sensitive) iv. Cyclic nucleotide activated cation channel (olfactory and visual sensory system); voltage-insensitive.v. Inward-recifier K+ channel (voltage-insensitive) gated by blocking particles in the intracellular side of the membrane.(most common from bacteria to mammals). c. Some voltage-sensitive K+ channels are activated slower than voltagesensitive Na+ channels and hence cause delayed opening of these K+ channels. d. Increased intracellular calcium concentrations can open some K+ channels, which can lead to repolarization membrane responses. e. Some chemically gated receptors can activate G-protein-mediated intracellular second messenger responses, closing some K+ channels, such as those in some muscarinic cholinergic receptors). More on this in synaptic transmission, and in the forthcoming Neurosciences module. 3. Calcium channels: a. Several types of channels with different activation and inactivation properties (Nice to know L,T,N,P,Q, and R types).

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b. N,P and Q types of calcium channels are important for neurotransmitter release from nerve terminals. c. Seizures may arise from a rapid discharge of cortical neurons which may be evoked by slow, low-amplitude depolarizations or action potentials produced by calcium channels.

4. Chloride channels a. Chemically gated chloride channels (directly activated by neurotransmitters) are involved in inhibitory post-synaptic potentials (IPSPs). b. [nice to know: voltage-gated Cl- channels recently discovered, but their role not yet clear in the nervous system.] c. Leaky or resting ion channels (background) are important for stabilizing the resting membrane, particularly in skeletal muscle. Pathologies involving Cl- channels may occur, such as in myotonia congenita, where depolarized, hyperexcitable muscles remain contracted. d. Cl- channels play an important function in regulating intracellular pH (Cl- /HCO3 exchanger) and cell volume.

VI.

What is the Nerve Action Potential ? Be able to draw an ACTION POTENTIAL, NAME the PHASES of an action potential, AND BEHAVIOR OF VOLTAGE-GATED CHANNELS. Note that action potentials occur in Included nerves, cardiac muscle, smooth muscle, and neuro-endocrine cells. The is an all-or-none, rapid, transient depolarization of the membrane potential from resting membrane potential (ranging from 40 t o 90 mV in different tissues) to about +20 mV to + + 35 mV. Be familiar with various symbols such as: G

I = current; : INa, IK, ICa.

= conductance: GNa, GK, GCa; An increase in sodium conductance ( GNa ) means an increased

flow of sodium ions across the semi-permeable membrane through the ion channels, usually inward. An inward sodium current INa also means the same thing, and there is a mathematical equation for that too. A. THE ROLE OF VOLTAGE-GATED ION-SPECIFIC CHANNELS IN THE GENESIS OF NERVE ACTION POTENTIALS (General information focusing on nerve): 1 Ion-specific channels: The all-or-none characteristic of the action potential is based on the behavior of the regulatory gates that cover the ion-specific channels present in electrically excitable cells. In nerve cells, there are two voltage-gated channels: one specific for Na+ ions and the other specific for K+ ions. 1.1 Regulation of the voltage-gated Na+ channel: The Na+ channel has two gating particles (an m -activation gate, and an h-inactivation gate. ) a.1.1.1 Both the m- and h-gates must be open for Na+ to flow through the Na+ channel. a.1.1.2 When the m-gate is open, the channel is said to be activated. a.1.1.3 When the h-gate is closed, the channel is said to be inactivated. 1.2 Regulation of the voltage-gated K+ channel: The K+ channel has one gating particle, the n - gate. a.1.2.1 The n-gate must be open for K+ to flow through the K+ channel. a.1.2.2 The K+ channel does not have an inactivation gate. .2 Voltage and time-dependency: Changes in the membrane potential (voltage-gating) cause the opening and closing of the gates of the voltage-gated ion channels mentioned above in a time-dependent fashion. 2.1 RESTING: When the membrane is at rest (-70 to 90 mV), almost all of the channels are closed. 2.1.1 The Na+ channel is closed by the m-gate, however the h-gate is in open position. In this case, the closed Na+ channel is available for excitation. 2.1.2 The K+ at this voltage range is closed by the n-gate. 2.2 THRESHOLD and UPSTROKE; OVERSHOOT: When the membrane is depolarized to threshold (approximately 65 to 60 mV), a positive (regenerative) process produces an ALL-or-NONE upstroke of the action potential. The m-gates of the Na+ channels open in

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response to the initial depolarization, producing further Na+ influx and greater depolarization (overshoot). 2.3 DOWNSTROKE: The downstroke follows the upstroke as part of the all-or-none response. This is due to the followihg ionic events: 2.3.1 Depolarization of the membrane (around + 35 mV) causes the inactivation of the Na+ channels (closing of the h-inactivation gates) , and Na+ influx through the voltage gated channels into the cell stops. 2.3.2 Increasing depolarization of the membrane slowly activates the K+ channels, and the K+ flows out of the cell, causing the membrane to repolarize. 2.4 UNDERSHOOT: The undershoot occurs due to the following events involving the voltagegated K+ channels: 2.4.1 The n-gates of the K+ channels close slowly as the membrane repolarizes; therefore the K+ conductance is higher at the end of the action potential than during the resting state of the membrane. This higher K+ conductance causes the membrane to hyperpolarize (the after-hyperpolarization, or after-potential) as the membrane potential becomes more negative than the original resting membrane potential. 2.4.1 Eventually, the n-gates of the K+ channels close and the membrane potential returns to its resting level. B. General Notes on the REFRACTORY PERIODS (Nerve): 1. ABSOLUTE REFRACTORY PERIOD (ARP): During this interval, another action potential cannot be elicited, regardless of the stimulus strength. The ARP begins at the start of the upstroke and extends into the downstroke. 1.1 during the upstroke, a second action potential cannot occur because the m (activation) gates are opening as fast as possible. 1.2.During the early portion of the downstroke, an action potential cannot occur because the Na+ channels are inactivated by the h (inactivation) gates. 1.3 The absolute refractory period ends when the number of inactivated Na+ channels is reduced by repolarization and another action potential can be initiated. The Na+ channels once again available for excitation when the h gates open during the downstroke. 2. RELATIVE REFRACTORY PERIOD (RRP): During this interval, a second action potential can be elicited if the stimulus is sufficient (greater than normal). The stimulus must be greater than normal because some Na+ channels are still inactivated and more K+ channels than normal are still open. The RRP begins when the ARP ends. The action potential elicited during this interval has a lower upstroke velocity and a lower overshoot potential thn does the normal potential. 2.1. these changes result from the increased number of inactivated Na+ channels and activated K+ channels that exist during the relative refractory period compared with the resting state. SYNTHESIS: Be able to draw a nerve action potential, and describe its phases. i. the nerve action potential is a transient depolarization of the membrane from its resting potential ( give a value ___?___ ) to about _____?_______. ii. The threshold potential is the membrane potential at which an action potential is initiated, opening up voltage-sensitive/gated Na+ channels producing an inward Na+ current. iii. Repolarization occurs because Na+ channel inactivation (Na+ current becomes zero at about + 20 to +35 mV, depending on tissues iv. Recovery from Na+ channel inactivation requires a few millisecond, during which time the membrane cannot be excited again. The absolute refractory period (2 3 msec) is the time from beginning of the action potential until Na+ channels recover from inactivation, during which the membrane is not excitable. v. Why does the action potential result in a small increase of sodium ions intracellularly and a small decrease of potassium intracellularly. How is this corrected by the Na+-K+ pump ? [ Compare with nerve action potential in terms of the general form of the following action potentials and ionic events involved:] a. Skeletal Muscle (read further to describe the action potentials): draw a skeletal muscle action potential and compare with nerve action potential. vi. The skeletal muscle cell action potential is similar to the nerve, and mirrors the changes in ion channel activity/ ion currents taking place in the nerve.

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b. Cardiac Muscle (read further to describe the action potentials): draw a typical cardiac muscle action potential, and describe its phases. i. What accounts for the plateau phase of the action potential of cardiac muscle ? c. Some Visceral Smooth Muscle (read further to describe the action potentials). i. In many visceral smooth muscle cells, there is an unstable resting membrane potential, and these cells exhibit spontaneous depolarizations ii. In some smooth muscle cells, such as that in gastric antrum smooth muscle, there is also an action potential similar to cardiac muscle, exhibiting a plateau phase. What accounts for its plateau phase?

VII.

What are the passive properties of the cell membrane ? a. Depend on the resistance and capacitance properties of the intra- and extracellular spaces and the plasma membrane. b. Responsible for the passive, longitudinal spread of electrical events, resulting in diminished voltage changes further away from the source of the changes (sometimes called the length or space constant).

VIII.

How is an action potential propagated in the nerve (action potential conduction) ? Definition of terms: Membrane resistance = m
Axoplasmic or intracellular resistance =

ri
= rm / ri

Membrane capacitance =

Cm = rm x cm

Length constant = ( read as lambda) ; Time constant =

(read as theta );

General cable properties: a. Action potential spreads along the axon by local currents which are dependent on the resistance and capacitance properties. b. The greater the length constant, the faster the action potential will spread (higher conduction velocity). A smaller length constant a lower conduction velocity. c. The greater the capacitance, the slower the action potential will spread (lower conduction velocity) . Smaller membrane capacitance higher conduction velocity (faster spread of action potential).. A. Unmyelinated axons: i. Unmyelinated axons have voltage-sensitive channels along the length of the axon. ii. They have a short length constant and high capacitance. iii. The action potential currents spread from one portion of the axonal membrane to activate the sodium channels of the neighboring portion of the axonal membrane. iv. Conduction velocity is slow (less than 2 meters per second). v. Repolarization occurs by activation of [delayed rectifier-type] potassium channels distributed along the length of the axon. vi. In unmyelinated fibers, the speed of propagation or conduction velocity is approximately or very roughly proportional to the square root of the axonal diameter:

C.V. =

diameter in microns

Myelinated axons: i. Myelin consists of the plasma membrane of oligodendrocyte or Schwann cells wrapping numerous times around the axon. ii. The internodal region is the axon region covered by myelin and is devoid of most voltage-sensitive ion channels. iii. The node of Ranvier is the gap between neighboring oligodendrocytes or Schwann cells and is where most of the voltage-sensitive ion channels are located.

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Myelin causes membrane capacitance to be reduced because it increases the distance between the two conductors the extracellular and intracellular compartments. Myelin increases the membrane resistance of the axon and thus increases the length (space) constant [ = m i , i.e., increases the length along the membrane in which the effect of the current spreads), The action potential current spreads ahead more than the length of two nodes of Ranvier, depolarizing and activating the voltage-sensitive Na+ channels in these nodes. Action potential conduction in myelinated nerves is called saltatory conduction or saltatory (jumping) propagation because the active currents jump mainly from one node to the next node. Synthesis 1: The conduction velocity is increased by myelin-induced decreased capacitance and increased membrane resistance (meaning increased length constant = m i) ; and this conduction velocity is directly dependent on the myelinated axonal diameter. A bigger diameter means a decreased axoplasmic / intracellular resistance to the flow of ions, thereby facilitating the propagation of an action potential along large-diameter, myelinated axons. Formula for computing or approximating conduction velocity of myelinated fibers: C.V. = 6 X DIAMETER of myelinated axon. Your unit for conduction velocity is in meters/sec (m/s). So a 15 micron-fiber in diameter has a conduction velocity = 90 m/s. Synthesis 2: Myelinated nerve fibers do not have many effective, voltage-sensitive K+ channels; therefore repolarization is rapidly mediated by passive redistribution of ions involving leaky (nongated, usally open) ion channels. Voltage-gated K+ channels in myelinated nerve fibers are not important in the repolarization process.

/ r

vi.

vii. viii.

/ r

ix.

x.

EFFECTS OF DEMYELINATION: Gradual destruction of the oligodendrocyte or Schwann cell results in demyelination observed in several disease entities, such as multiple sclerosis. ii. As the myelin is reduced, the axonal capacitance increases and membrane resistance is i. reduced, which reduces the space constant ( = m i ), causing a decreased conduction velocity. As the demyelination continues, the depolarizing currents fail to spread sufficiently from one node to the next node where the next cluster of voltage-sensitive Na+ channels are located. Thus threshold depolarization does not occur in the next node, causing cessation of action potential conduction. If some remyelination occurs or if sodium channels become distributed in the internodal regions as in unmyelinated axons, some conduction may return at a greatly reduced conduction velocity. Initiation of an action potential : 1. Where are action potentials naturally initiated ? a. In neurons of the central nervous system and in neurons of the autonomic ganglia, they occur at the region of the axon hillock and the initial segment of the axon, which is the region of lowest threshold. From the axon hillock and initial segment, the action potential spreads in two directions down the axon (orthodromic conduction) and back into the cell body and into the dendrites (antidromic conduction). However chemical transmission from one neuron to another neuron or effector organ is only possible through one direction through the synapses from the presynaptic terminals to the post-synaptic cell (axo-axonic, axodendritic, axo-somatic synapses). No transmission takes place from a post-synaptic cell to a presynaptic terminal or neuron. b. In the spike generator region of the sensory nerve terminals (more on this in sensory physiology). 2. Why do large-diameter axons have lower thresholds of activation than small-diameter axons, as shown by increasing the intensity of electrical stimulation of a nerve bundle comprising a mixture of small- and largediameter fibers ?

/ r

iii.

iv.

II.

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The large-diameter axons have a smaller internal resistance, and more current will flow through the larger axons than the smaller axons. , Thus, for a given electrical stimulus intensity, larger axons are more likely to reach threshold, that is, they are more excitable than smaller axons. More on this in sensory physiology during the second semester.