Differential blockade of rat alpha(3)beta(4) and alpha(7) neuronal nicotinic receptors by omega-conotoxin MVIIC, omega-conotoxin GVIA and diltiazem

1 Rat alpha(3)beta(4) or alpha(7) neuronal nicotinic acetylcholine receptor s (AChRs) were expressed in Xenopus laevis oocytes, and the effects of vari ous toxins and non-toxin Ca2+ channel blockers studied. Nicotinic AChR curr ents were elicited by 1 s pulses of dimethylphenylpiperazinium (DMPP, 100 m u M) applied at regular intervals. 2 The N/P/Q-type Ca2+ channel blocker omega-conotoxin MVIIC inhibited alpha (3)beta(4) currents with an IC50 of 1.3 mu M; the blockade was non-competit ive and reversible. The alpha(7) currents were unaffected. 3 At 1 mu M, omega-conotoxin GVIA (N-type Ca2+ channel blocker) inhibited b y 24 and 20% alpha(3)beta(4) and alpha(7) currents, respectively. At 1 mu M , omega-agatoxin IVA (a P/Q-type Ca2+ channel blocker) did not affect alpha (7) currents and inhibited alpha(3)beta(4) currents by only 15%. 4 L-type Ca2+ channel blockers furnidipine, verapamil and, particularly, di ltiazem exhibited a preferential blocking activity on alpha(3)beta(4) nicot inic AChRs. 5 The mechanism of alpha(3)beta(4) currents blockade by omega-conotoxins an d diltiazem differed in the following aspects: (i) the onset and reversal o f the blockade was faster for toxins; (ii) the blockade by the peptides was voltage-dependent, while that exerted by diltiazem was not; (iii) diltiaze m promoted the inactivation of the current while omega-toxins did not. 6 These data show that, at concentrations currently employed as Ca2+ channe l blockers, some of these compounds also inhibit certain subtypes of nicoti nic AChR currents. Our data calls for caution when interpreting many of the results obtained in neurons and other cell types, where nicotinic receptor and Ca2+ channels coexist.