This is the basic unit ('bit') of information processing in the nervous system. It is a transient electrical signal generated by the opening of voltage-gated Na+ channels. These are normally shut at rest (or largely so), but are opened when the nerve cell membrane is depolarised by (e.g.) an excitatory transmitter. Since the entry of Na+ ions further depolarises the membrane, so opening more Na+ channels, the process becomes regenerative once the threshold potential is exceeded: this is the potential at which the rate of Na+ entry exceeds the rate of K+ efflux (and/or Cl~ entry). The membrane
potential then moves transiently toward (but does not usually quite reach) the Na+ equilibrium potential (£Na ~ +50 to + 70 mV; Fig. 2.2)— i.e. the membrane potential is reversed to inside-positive. Repolarization results (in the first instance) from the inactivation of the Na+ channels — that is, as the depolarisation is maintained, the channels close again (though at a slower rate than that at which they open). Recovery then requires that they progress back from the inactivated state to the resting closed state: this takes a little time, so the action potential becomes smaller and eventually fails during high frequency stimulation or during sustained depolarisation — a process of accommodation.
Local anaesthetics and some anti-epileptic drugs such as phenytoin and carbemaze-pine act by blocking Na+ channels. Many of these have a higher affinity for the inactivated state of the Na+ channel than for the resting or open states. Hence, by promoting inactivation, they selectively reduce high-frequency nerve impulses ('use-dependence'). This provides a rationale for the use of phenytoin and carbemazepine in controlling epileptic discharges.
In unmyelinated fibres (including the squid axon, where the ionic currents responsible for the action potential were first elucidated, see Fig. 2.2), and in unmyelinated regions of neurons, such as dendrites, somata and axon terminals, action potential repolarisation is accelerated by the delayed opening of additional voltage-gated K+ channels — so-called delayed rectifier K+ channels. These may be sustained or transient (inactivating) in kinetic behaviour. Since they take a few milliseconds to close as the potential recovers, in addition to hastening repolarisation, current flow through these channels leads to a transient after-hyperpolarisation ('undershoot') following each action potential. Where the action potential leads to the opening of voltage-gated Ca2+ channels (as in nerve terminals and neuron somata or dendrites — see below), the entry of Ca2+ also induces the rapid opening of large (100-200 pS in symmetrical high [K+]) conductance ('BK') Ca2+-activated K+ channels, which can also accelerate action potential repolarisation. However, K+ channels are normally absent from nodes of Ranvier and action potential repolarisation in myelinated fibres results solely from Na+ channel inactivation. Thus, blocking K+ channels with drugs such as tetraethyl-ammonium or 4-aminopyridine (Fig. 2.3) does not affect conduction along myelinated fibres (though they can increase transmitter release, by prolonging the action potential in unmyelinated nerve terminals). They can also improve conduction in myelinated fibres following demyelination (e.g. in multiple sclerosis). This is because the action potential now has to be conducted along the demyelinated segments of the fibres (continuous conduction), instead of 'jumping' from node to node (saltatory conduction). (This is assisted by the spread of Na+ channels from the nodes along the internodes after demyelination.) Since K+ channels are normally present along internodal segments of myelinated fibres and the internodal Na+ channel density is relatively low (even after demyelination), current through the K+ channels tends to 'shunt' the Na+ current and block internodal action potential conduction. Cooling the nerve has a similar effect to blocking K+ channels: hence MS patients are very sensitive to temperature.
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