книги студ / color atlas of physiology 5th ed[1]. (a. despopoulos et al, thieme 2003)

Propagation of Action Potentials in

Nerve Fiber

Electrical current flows through a cable when voltage is applied to it. The metal wire inside the cable is well insulated and has very lowlevel resistance, reducing current loss to a minimum. As a result, it can conduct electricity over long distances. Nerve fibers, especially unmyelinated ones (!p. 42), have a much greater internal longitudinal resistance (Ri) and are not well insulated from their surroundings. Therefore, the cable-like, electrotonic transmission of neural impulses dwindles very rapidly, so the conducted impulses must be continuously “refreshed” by generating new action potentials (!p. 46).

Propagation of action potentials: The start of an action potential is accompanied by a brief influx of Na+ into the nerve fiber (!A1a). The cell membrane that previously was inside negative now becomes positive ( + 20 to + 30 mV), thus creating a longitudinal potential difference with respect to the adjacent, still unstimulated nerve segments (internal –70 to –90 mV; !p. 44). This is followed by a passive electrotonic withdrawal of charge from the adjacent segment of the nerve fiber, causing its depolarization. If it exceeds threshold, another action potential is created in the adjacent segment and the action potential in the previous segment dissipates (!A1b).

Because the membrane acts as a capacitor, the withdrawal of charge represents a capacitating (depolarizing) flow of charge that becomes smaller and rises less steeply as the spatial distance increases. Because of the relatively high Ri of nerve fiber, the outward loops of current cross the membrane relatively close to the site of excitation, and the longitudinal current decreases as it proceeds towards the periphery. At the same time, depolarization increases the driving force (= Em – EK; !p. 32) for K+ outflow. K+ fluxing out of the cell therefore accelerates repolarization. Hence, distal action potentials are restricted to distances from which the capacitative current suffices to depolarize the membrane quickly and strongly enough. Otherwise, the Na+ channels will be deactivated before the threshold potential is reached (!p. 46).

Action potentials normally run forward (orthodromic) because each segment of nerve fiber becomes refractory when an action potential passes (!A1b and p. 46). If, however, the impulses are conducted backwards (antidromic) due, for example, to electrical stimulation of nerve fibers from an external source (!p. 50), they will terminate at the next synapse (valve-like function, !p. 42).

Although the continuous generation of action potentials in the immediately adjacent fiber segment guarantees a refreshed signal, this process is rather time-consuming (!B1). The conduction velocity, θ, in unmyelinated (type C) nerve fibers (!C) is only around 1 m/s. Myelinated (types A and B) nerve fibers (!C) conduct much faster (up to 80 m/s = 180 mph in humans). In the internode regions, a myelin sheath (!p. 42) insulates the nerve fibers from the surroundings; thus, longitudinal currents strong enough to generate action potentials can travel further down the axon (ca. 1.5 mm) (!A2). This results in more rapid conduction because the action potentials are generated only at the unmyelinated nodes of Ranvier, where there is a high density of Na+ channels. This results in rapid, jump-like passage of the action potential from node to node (saltatory propagation). The saltatory length is limited since the longitudinal current (1 to 2 nA) grows weaker with increasing distance (!B2). Before it drops below the threshold level, the signal must therefore be refreshed by a new action potential, with a time loss of 0.1 ms.

Since the internal resistance, Ri, of the nerve fiber limits the spread of depolarization, as described above, the axon diameter (2r) also affects the conduction velocity, θ (!C). Ri is proportional to the cross-sectional area of the nerve fiber (πr2), i.e., Ri !1/r2. Thick fibers therefore require fewer new APs per unit of length, which is beneficial for θ. Increases in fiber diameter are accompanied by an increase in both fiber circumference (2πr) and membrane capacity, K (K !r). Although θ decreases, the beneficial effect of the smaller Ri predominates because of the quadratic relationship.

Motor End-plate

The transmission of stimuli from a motor axon to a skeletal muscle fiber occurs at the motor end-plate, MEP (!A), a type of chemical synapse (!p. 50ff.). The transmitter involved is acetylcholine (ACh, !cf. p. 82), which binds to the N(nicotinergic)-cholinoceptors of the subsynaptic muscle membrane (!A3). N-cholino- ceptors are ionotropic, that is, they also function as ion channels (!A4). The N-cholinocep- tor of the MEP (type NM) has 5 subunits (2α, 1", 1γ, 1δ), each of which contains 4 membranespanning α-helices (!p. 14).

The channel opens briefly (!B1) (for approx. 1 ms) when an ACh molecule binds to the two α-subunits of an N-cholinoceptor (!A4). Unlike voltage-gated Na+-channels, the openprobability po of the NM-cholinoceptor is not increased by depolarization, but is determined by the ACh concentration in the synaptic cleft

(!p. 50 ff.).

The channel is specific to cations such as Na+, K+, and Ca2+. Opening of the channel at a resting potential of ca. !90 mV leads mainly to an influx of Na+ ions (and a much lower outflow of K+; !pp. 32 ff. and 44). Depolarization of the subsynaptic membrane therefore occurs: endplate potential (EPP). Single-channel currents of 2.7 pA (!B1) are summated to yield a miniature end-plate current of a few nA when spontaneous exocytosis occurs and a vesicle releases a quantum of ACh activating thousands of NM-cholinoceptors (!B2). Still, this is not enough for generation of a postsynaptic action potential unless an action potential transmitted by the motor neuron triggers exocytosis of around a hundred vesicles. This opens around 200,000 channels at the same time, yielding a neurally induced end-plate current (IEP) of ca. 400 nA (!B3). End-plate current, IEP, is therefore dependent on:

the number of open channels, which is equal to the total number of channels (n) times the open-probability (po), where po is determined by the concentration of ACh in the synaptic cleft (up to 1 mmol/L);

the single-channel conductance γ (ca.

30 pS);

and, to a slight extent, the membrane potential, Em, since the electrical driving

“force” (= Em –ENa,K; !p. 32 ff.) becomes smaller when Em is less negative.

ENa,K is the common equilibrium potential for Na+ and K+ and amounts to approx. 0 mV. It is also called the reversal potential because the direction of IEP (= INa + IK), which enters the cell when Em is negative (Na+ influx " K+ outflow), reverses when Em is positive (K+ outflow " Na+ influx). As a result,

Because neurally induced EPPs in skeletal muscle are much larger (depolarization by ca. 70 mV) than neuronal EPSPs (only a few mV; !p. 50 ff.), single motor axon action potentials are above threshold. The EPP is transmitted electrotonically to the adjacent sarcolemma, where muscle action potentials are generated by means of voltage-gated Na+ channels, resulting in muscle contraction.

Termination of synaptic transmission in MEPs occurs (1) by rapid degradation of ACh in the synaptic cleft by acetylcholinesterase localized at the subsynaptic basal membrane, and

(2) by diffusion of ACh out of the synaptic cleft (!p. 82).

A motor end-plate can be blocked by certain poisons and drugs, resulting in muscular weakness and, in some cases, paralysis. Botulinum neurotoxin, for example, inhibits the discharge of neurotransmitters from the vesicles, and α-bungarotoxin in cobra venom blocks the opening of ion channels. Curare-like substances such as (+)-tubocurarine are used as muscle relaxants in surgical operations. They displace ACh from its binding site (competitive inhibition) but do not have a depolarizing effect of their own. Their inhibitory effect can be reversed by cholinesterase inhibitors such as neostigmine (decurarinization). These agents increase the concentration of ACh in the synaptic cleft, thereby displacing curare. Entry of anticholinesterase agents into intact synapses leads to an increase in the ACh concentration and, thus, to paralysis due to permanent depolarization. ACh-like substances such as suxamethonium have a similar depolarizing effect, but decay more slowly than ACh. In this case, paralysis occurs because permanent depolarization also permanently inactivates Na+ channels near the motor end-plate on the sarcolemma (!p. 46).