the GABA-A ionophore channel, and the glycine receptor—the latter two both being
Cl−channels—show about 50% homology, have closely related subunits, and are all
organized with four transmembrane domains. These three proteins constitute one important
family of channel receptors.
Another major channel family is the voltage-gated ion channel family. The sodium
and calcium channels have four structurally similar regions with each region consisting
of six transmembrane domains; within each of the four regions exists an Arg-X-X
motif, where X is a hydrophobic amino acid. This Arg-rich zone is thought to be the
voltage sensor that transforms electric fields into conformational changes. The potassium
channel is much smaller, but part of it is 50% homologous with the voltage sensor of
the Na+and Ca^2 +channels. The K+channel is believed to be the most ancient one and
may have developed into the more modern structures by gene duplication.
7.4.1.1 Voltage-Gated Ion Channels in Neuronal Membranes
Na+and K+ions are transported independently across neuronal membranes. The discovery
of the highly specific effects of some channel-blocking neurotoxins has helped to
clarify our concept of these ion channels. Tetrodotoxin (7.1, TTX) is found in the liver
and ovaries of the puffer fishes and in the eggs of some amphibians (e.g., the newt
Taricha). The potential dangers notwithstanding, the flesh of the puffer fish (Fugu fish)
is a delicacy in Japan, prepared by licensed chefs. Yet, despite their skills, there are quite a
few losers every year in this gastronomic game of Russian roulette.Saxitoxin (7.2, STX)
is produced by marine dinoflagellates of the genera GonyaulaxandGymmodinium,
important members of the phytoplankton. Under certain environmental conditions they
multiply explosively, causing “red tides.” These algae are consumed by shellfish, which
remain unaffected by the poison but can produce extremely toxic effects known as
paralytic shellfish poisoning in humans who consume as little as 1 mg of STX in the
shellfish.
Both TTX and STX exert their effect by blocking the inward Na+current during neu-
ronal depolarization while not affecting the outward K+current. The toxins are effective
only if applied from the outside; they are ineffective if perfused into the axon. Both tox-
ins seem to be Na+-channel specific by virtue of their guanidinium groups, since guani-
dinium ions can pass through Na+channels and interact with the open ion channel only.
The affinity of both toxins is very high, ranging from 2 to 8 nM.
414 MEDICINAL CHEMISTRY