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NEUROPHARMACOLOGY

Iptakalim as a Human Nicotinic Acetylcholine Receptor Antagonist

Divisions of Neurology (J.H., J.W.) and Neurobiology (K.L., R.J.L.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; Department of Pharmacology, Nanjing Medical University, Nanjing, People's Republic of China (G.H., J.H., J.W.); and Department of Cardiovascular Pharmacology, Institute of Pharmacology and Toxicology, Beijing, People's Republic of China (H.W., J.W.)

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 42-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 42-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to 42-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 42-nAChR function. By comparison, 7-nAChRs were less sensitive than 42-nAChRs to Ipt acting as an antagonist. Thus, 42-nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.

Address correspondence to: Dr. Jie Wu, Division of Neurology, Barrow Neurological Institute, 350 West Thomas Rd., Phoenix, AZ 85013-4496. E-mail: jwu2{at}chw.edu