The Acetylcholine Receptor and Its Ionic Channel as Targets for Drugs and Toxins

摘要

The overall objective of this study was to establish the pharmacology of the ionic channel of the peripheral nicotinic acetylcholine (ACh) receptor and to understand the mechanism by which this receptor controls the selective translocation of cations across membranes. The combination of electrophysiological techniques with biochemical ones helped us to understand the molecular properties of this ACh-receptor/channel and its interactions with drugs and toxins and also determine the cases where it may act as a secondary target for the action of a variety of drugs including anticholinesterases. Electrophysiological techniques were used to analyze the characteristics of endplate currents and channel properties of mammalian and frog skeletal muscles, while biochemical techniques were used to study the molecular characteristics and drug specificities of the ACh-receptor/channel of the electric organ of the electric ray, Torpedo sp. The data obtained suggest that the ACh-receptor/channel molecule carries two kinds of binding sites: receptor sites that bind ACh and alpha-bungarotoxin in a voltage-independent and almost temperature-independent manner, and channel sites that bind a variety of drugs in a voltage- and temperature-dependent manner, and are more sensitive than the receptor sites to treatment by the detergent Triton X-100 and sulfhydryl reducing and alkylating agents. The ACh-receptor/channel molecule undergoes different ligand/induced conformations, which we could detect by monitoring the apparent rates of binding of radiolabeled drugs to the channel sites.