Estimation of Drug Affinities for Calcium Channel Conformational States

Abstract

It was suggested about 20 years ago that drugs can bind with different strengths to resting (R), open (0), and inactivated (I) conformational states of ionic channels (Strichartz, 1973; Courtney, 1975; Khodorov et al., 1976; Hille, 1977; Hondeghem and Katzung, 1977). In the 1980s this concept was applied to the mechanism of action of calcium channel ligands on L-type calcium channels in heart (Bean, 1984; Sanguinetti and Kass, 1984; McDonald et al., 1984) and smooth muscle cells (Bean et al., 1986; Klöckner and Isenberg, 1986; Hering et al., 1988). Patch-clamp studies in single cells enabled an accurate description of drug-induced changes in whole-cell current kinetics and single-channel behavior and subsequently the interpretation of electrophysiological data in terms of channel state models. Comparative studies of the action of 1,4dihydropyridine (1,4-DHP), phenylalkylamine (PAA), and benzothiazepine (BTA) in single cardiomyocytes revealed remarkable differences with respect to the dependence of drug action on the frequency of depolarization and membrane potential (Lee and Tsien, 1983; Uehra and Hume, 1985). In analogy to the effect of local anesthetics on sodium channels (Khodorov, 1981), the action of antagonist 1,4-DHPs has been interpreted as a high-affinity drug binding to inactivated calcium channels (Bean, 1984; Sanguinetti and Kass, 1984). The action of 1,4-DHPs, however, can be distinguished from “lidocain-like” drugs, as the 1,4-DHP effect on calcium channels is not significantly enhanced by repetitive membrane depolarization (Lee and Tsien, 1983; Uhera and Hume, 1985; Hering et al., 1988). A strong dependence on the “use of calcium channels,” i.e. activation of channels by test pulses, is evident for PAA antagonists. Their action seems to be closely related to the open conformational state (McDonald et al., 1984; Oyama et al., 1987; Hering et al., 1989).