Effects Of Diltiazem On Human Nicotinic Acetylcholine And Gaba(A) Receptors
Effects of the L-type calcium channel antagonist diltiazem on recombinant human GABA(A) receptor (Î±1Î²2Î³2s) or on muscle (Î±1Î²1Î´Î³ and Î±1Î²1Î´Îµ) or neuronal (Î±7 and Î±4Î²2) nicotinic acetylcholine receptors expressed in Xenopus oocytes were examined using two-electrode voltage-clamp. Diltiazem inhibited the function of both muscle and neuronal nicotinic receptors, but it had no effect on GABA(A) receptors. The extent of functional inhibition of nicotinic receptors depended on the receptor subtype, and the order of inhibition potency by diltiazem was Î±7>Î±4Î²2â‰ƒÎ±1Î²1Î´Î³â‰ƒÎ±1Î²1Î´Îµ. Inhibition of Î±7 receptor function was non-competitive and voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely) binding of 125I-Î±-bungarotoxin to heterologously expressed Î±7 receptors 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-type Ca2+ channels also fully inhibited Î±7 receptor function and partially inhibited 125I-Î±-bungarotoxin binding to Î±7 receptors, but was less potent than diltiazem. Effects on both Î±7 receptor function and 125I-Î±-bungarotoxin binding by verapamil plus diltiazem suggest separate sites for verapamil and diltiazem on Î±7 receptors. These results provide further evidence that L-type Ca2+ channel drugs inhibit ligand-gated cationic 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. Copyright (C) 2000 Elsevier Science Ltd.
Digital Object Identifier (DOI)
Houlihan, L. M.; Slater, E. Y.; Beadle, D. J.; Lukas, R. J.; and Bermudez, I., "Effects Of Diltiazem On Human Nicotinic Acetylcholine And Gaba(A) Receptors" (2000). Neurobiology. 213.