title: Iptakalim as a human nicotinic acetylcholine receptor antagonist.
abstract: 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 steady-state whole-cell current amplitudes mediated by human alpha4beta2-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 alpha4beta2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to alpha4beta2-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 alpha4beta2-nAChR function. By comparison, alpha7-nAChRs were less sensitive than alpha4beta2-nAChRs to Ipt acting as an antagonist. Thus, alpha4beta2-nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.
authors.affiliation: Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013-4496, USA. jwu2@chw.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Kari
authors.initials: K
authors.lastname: Lindenberger
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
mesh_terms: D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011437:Propylamines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011437:Propylamines; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C082748:epibatidine