Effects of diltiazem on human nicotinic acetylcholine and GABA(A) receptors

Effects of the L-type calcium channel antagonist diltiazem on recombinant h uman GABA(A) receptor (alpha1 beta2 gamma 2s) or on muscle (alpha1 beta1 de lta gamma and alpha1 beta1 delta epsilon) or neuronal (alpha7 and alpha4 be ta2) nicotinic acetylcholine receptors expressed in Xenopus oocytes were ex amined using two-electrode voltage-clamp. Diltiazem inhibited the function of both muscle and neuronal nicotinic receptors, but it had no effect on GA BA(A) receptors. The extent of functional inhibition of nicotinic receptors depended on the receptor subtype, and the order of inhibition potency by d iltiazem was alpha7>alpha4 beta2 similar or equal to alpha1 beta1 delta gam ma similar or equal to alpha1 beta1 delta epsilon. Inhibition of alpha7 rec eptor function was non-competitive and voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely ) binding of I-125-alpha -bungarotoxin to heterologously expressed alpha7 r eceptors in mammalian cells. Pre-incubation in diltiazem before concomitant application with acetylcholine increased inhibition of function and slowed recovery from inhibition. Verapamil, a phenylalkylamine antagonist of L-ty pe Ca2+ channels also fully inhibited alpha7 receptor function and partiall y inhibited I-125-alpha -bungarotoxin binding to alpha7 receptors, but was less potent than diltiazem. Effects on both alpha7 receptor function and I- 125-alpha -bungarotoxin binding by verapamil plus diltiazem suggest separat e sites for verapamil and diltiazem on alpha7 receptors. These results prov ide further evidence that L-type Ca2+ channel drugs inhibit ligand-gated ca tionic channels and suggest that caution should be applied when using these compounds to study systems in which L-type Ca2+ channels and ligand-gated cationic channels co-exist. (C) 2000 Elsevier Science Ltd. All rights reser ved.