Macromolecular sites for specific neurotoxins and drugs on chemosensitive synapses and electrical excitation in biological membranes.
The present review deals with the molecular mechanisms and elementary phenomena underlying the activation of the voltage- and chemo-sensitive membrane macromolecules: sodium- and potassium-ion channels and nicotinic ACh receptors and their associated ion channel. To achieve an understanding of their various kinetics and conformational states, a number of novel alkaloids, BTX, HTXs, gephyrotoxins, and certain psychotomimetic drugs such as phencyclidine, and many other pharmacologically active agents have been used. Biochemical assays and various electrophysiological techniques have been used in a number of biological preparations--e.g., Torpedo membranes, brain synaptosomes, amphibian and mammalian neuromuscular preparations--to describe the action of such agents. The availability of BTX and scorpion toxins together with aconitine and veratridine as activators and TTX and STX as antagonists of the voltage-sensitive sodium channels, made possible the identification and the physiological and pharmacological characterization of these channels. These studies provided the basis for understanding the mechanisms underlying electrical excitability and culminated, more recently, in the purification and reconstitution of sodium channels from rat brain and in the successful cloning of these channels with the elucidation of their primary structure. We now know that the sodium channel has a molecular mass of 316,000 daltons, consists of five subunits, and has multiple sites for various ligands. In contrast to sodium channels, various classes of potassium channels (inward and outward rectifier potassium channels and Ca(2+)-activated potassium channels) have been described. Unlike the sodium channels, there are no known specific activators for potassium channels. However, a number of potassium channel blockers such as 4-aminopyridine, HTX, histamine, and norepinephrine have been identified which complement the varying types of potassium channels in different neurons. One class of potassium channel blockers with profound medical and social implications comprises PCP and its analogues. The blockade of the potassium-induced 86Rb+ efflux from brain cells, the resulting prolongation of muscle and nerve action potentials, and the increase in transmitter release observed with PCP and some analogues are all highly suggestive of a role for the potassium channel in the behavioral effects of these drugs and its potential involvement in schizophrenia. A number of toxic principles of both plant and animal origin played a significant role in the development of our knowledge about the nAChR.(ABSTRACT TRUNCATED AT 400 WORDS)
Albuquerque
E X
EX
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
Daly
J W
JW
Warnick
J E
JE
D000818:Animals; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
D007473:Ion Channels; D009498:Neurotoxins; D011950:Receptors, Cholinergic; D011955:Receptors, Drug