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 (KATP) 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 Î±4Î²2-nAChRs 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 Î±4Î²2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to Î±4Î±2-nAChRs suggest a noncompetitive mechanism of antagonism. Other studies discount effects of Ipt on nAChR internalization or involvement of KATP channels in Ipt-induced inhibition of Î±4Î²2-nAChR function. By comparison, Î±7-nAChRs were less sensitive than Î±4Î²2-nAChRs to Ipt acting as an antagonist. Thus, Î±4Î²2-nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs. Copyright Â© 2006 by The American Society for Pharmacology and Experimental Therapeutics.
Journal of Pharmacology and Experimental Therapeutics
Digital Object Identifier (DOI)
Hu, Jun; Lindenberger, Kari; Hu, Gang; Wang, Hai; Lukas, Ronald J.; and Wu, Jie, "Iptakalim As A Human Nicotinic Acetylcholine Receptor Antagonist" (2006). Neurobiology. 242.