Iptakalim as a human nicotinic acetylcholine receptor antagonist

Nicotinic acetylcholine receptors ( nAChRs) play many critical roles in nervous system function and have been implicated in a variety of diseases. Drugs acting at nAChRs, perhaps in nAChR subtype-selective manners, can be used to dissect receptor function and perhaps as medications. In the present study, we used patch-clamp whole-cell recording and pharmacological manipulations to evaluate effects of iptakalim hydrochloride ( Ipt), which is a drug reported to act as an ATP-sensitive potassium ( K-ATP) channel opener, on selected human nAChRs heterologously expressed in the native nAChR-null SH-EP1 human epithelial cell line. Ipt reduced both peak and steadystate whole-cell current amplitudes mediated by human alpha 4 beta-2nAChRs in response to nicotinic agonists. It also accelerated current decay, caused a decline in apparent efficacy of agonists, and acted in voltage-and use-dependent manners at alpha 4 beta 2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to alpha 4 beta 2-nAChRs suggest a noncompetitive mechanism of antagonism. Other studies discount effects of Ipt on nAChR internalization or involvement of K ATP channels in Ipt-induced inhibition of alpha 4 beta 2-nAChR function. By comparison, alpha 7-nAChRs were less sensitive than alpha 4 beta 2-nAChRs to Ipt acting as an antagonist. Thus, alpha 4 beta-2nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.