The formulation of the ionic hypothesis of nervous conduction by HODGKIN and
HUXLEY (1952; see also HODGKIN, 1964), especially with its emphasis on the
voltage-clamping technique, made it clear that the action potential in excitable
membrane is generated by two ionic currents: an early sodium current and a
late potassium current. The nervous membrane, however, is not uniformly
permeable to the two cations, sodium and potassium; instead, the currents flow
at certain specialized patches or sites on the membrane rather than across all
parts of it. Furthermore, pharmacological evidence shows that the two currents
flow across the membrane at two different types of sites. For example, the tetra￾ethylammonium ion completely blocks the late potassium current both in the squid
giant axon (by internal application, ARMSTRONG and BINSTOCK, 1965) and in frog
myelinated nerve fibers (by application, externally, HILLE, 1967; and internally,
ARMSTRONG and HILLE, 1972). Similarly — and more germanely for the present
review — the early sodium current can be prevented either by saxitoxin or by
tetrodotoxin. The toxin has to be applied externally, for example, to lobster
giant axons and frog myelinated nerve (NARAHASHI et al., 1964; HILLE, 1968a),
for it is quite ineffective when applied internally to the squid giant axon
(NARAHASHI et al., 1966). These two toxins are important, not so much because they
are active in extremely low concentrations-they are in fact among the most
potent nonprotein poisons known; rather it is because their action is so highly
specific. Unlike the local anesthetic agents, for example, which block the sodium
current in low concentrations but which in higher concentrations also block the
potassium current, the two toxins, saxitoxin and tetrodotoxin, even in relatively
high concentrations, have only a single known pharmacological action, namely
the specific blocking of sodium channels. It is because of this specificity that the
extent to which these toxins are bound to conducting tissue can be used as a
measure of the number of sodium channels. They are in fact used as specific
chemical markers for this important membrane component of excitable tissue
(see RITCHIE, 1975a).