Differential blockade of rat α 3 β 4 and α 7 neuronal nicotinic receptors by ω‐conotoxin MVIIC, ω‐conotoxin GVIA and diltiazem

Rat α 3 β 4 or α 7 neuronal nicotinic acetylcholine receptors (AChRs) were expressed in Xenopus laevis oocytes, and the effects of various toxins and non‐toxin Ca 2+ channel blockers studied. Nicotinic AChR currents were elicited by 1 s pulses of dimethylphenylpiperazinium (DMPP, 100 μ M ) applied at regular intervals. The N/P/Q‐type Ca 2+ channel blocker ω‐conotoxin MVIIC inhibited α 3 β 4 currents with an IC 50 of 1.3 μ M ; the blockade was non‐competitive and reversible. The α 7 currents were unaffected. At 1 μ M , ω‐conotoxin GVIA (N‐type Ca 2+ channel blocker) inhibited by 24 and 20% α 3 β 4 and α 7 currents, respectively. At 1 μ M , ω‐agatoxin IVA (a P/Q‐type Ca 2+ channel blocker) did not affect α 7 currents and inhibited α 3 β 4 currents by only 15%. L‐type Ca 2+ channel blockers furnidipine, verapamil and, particularly, diltiazem exhibited a preferential blocking activity on α 3 β 4 nicotinic AChRs. The mechanism of α 3 β 4 currents blockade by ω‐conotoxins and diltiazem differed in the following aspects: (i) the onset and reversal of the blockade was faster for toxins; (ii) the blockade by the peptides was voltage‐dependent, while that exerted by diltiazem was not; (iii) diltiazem promoted the inactivation of the current while ω‐toxins did not. These data show that, at concentrations currently employed as Ca 2+ channel blockers, some of these compounds also inhibit certain subtypes of nicotinic AChR currents. Our data calls for caution when interpreting many of the results obtained in neurons and other cell types, where nicotinic receptor and Ca 2+ channels coexist.British Journal of Pharmacology (1999) 127 , 1375–1387; doi: 10.1038/sj.bjp.0702692