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NEUROPHARMACOLOGY

Iptakalim Modulates ATP-Sensitive K⁺ Channels in Dopamine Neurons from Rat Substantia Nigra Pars Compacta

Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona (J.W., J.H., J.D., Q.L., K.-C.Y.); Department of Cardiovascular Pharmacology, Institute of Pharmacology and Toxicology, Beijing, People's Republic of China (J.W., Y.-P.C., H.W.); Department of Medical Technology, Hirosaki University School of Health Science, Hirosaki, Japan (T.T.); Department of Physiology I, Hirosaki University School of Medicine, Hirosaki, Japan (S.S., M.W.); Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona (P.A.S.); and Department of Pharmacology, Nanjing University of Medical Science, Nanjing, People's Republic of China (J.W., J.H., G.H.)

Iptakalim, a novel cardiovascular ATP-sensitive K⁺ (K_ATP) channel opener, exerts neuroprotective effects on dopaminergic (DA) neurons against metabolic stress-induced neurotoxicity, but the mechanisms are largely unknown. Here, we examined the effects of iptakalim on functional K_ATP channels in the plasma membrane (pm) and mitochondrial membrane using patch-clamp and fluorescence-imaging techniques. In identified DA neurons acutely dissociated from rat substantia nigra pars compacta (SNc), both the mitochondrial metabolic inhibitor rotenone and the sulfonylurea receptor subtype (SUR) 1-selective K_ATP channel opener (KCO) diazoxide induced neuronal hyperpolarization and abolished action potential firing, but the SUR2B-selective KCO cromakalim exerted little effect, suggesting that functional K_ATP channels in rat SNc DA neurons are mainly composed of SUR1. Immunocytochemical staining showed a SUR1-rather than a SUR2B-positive reaction in most dissociated DA neurons. At concentrations between 3 and 300 µM, iptakalim failed to hyperpolarize DA neurons; however, 300 µM iptakalim increased neuronal firing. In addition, iptakalim restored DA neuronal firing during rotenone-induced hyperpolarization and suppressed rotenone-induced outward current, suggesting that high concentrations of iptakalim close neuronal K_ATP channels. Furthermore, in human embryonic kidney 293 cells, iptakalim (300-500 µM) closed diazoxide-induced Kir6.2/SUR1 K_ATP channels, which were heterologously expressed. In rhodamine-123-preloaded DA neurons, iptakalim neither depolarized mitochondrial membrane nor prevented rotenone-induced mitochondrial depolarization. These data indicate that iptakalim is not a K_ATP channel opener in rat SNc DA neurons; instead, iptakalim is a pm-K_ATP channel closer at high concentrations. These effects of iptakalim stimulate further pharmacological investigation and the development of possible therapeutic applications.

Address correspondence to: Dr. Jie Wu, Neurophysiology Laboratory, Neurology Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013-4496. E-mail: Jie.Wu{at}chw.edu

This article has been cited by other articles:

				N. Misaki, X. Mao, Y.-F. Lin, S. Suga, G.-H. Li, Q. Liu, Y. Chang, H. Wang, M. Wakui, and J. Wu Iptakalim, a Vascular ATP-Sensitive Potassium (KATP) Channel Opener, Closes Rat Pancreatic beta-Cell KATP Channels and Increases Insulin Release J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 871 - 878. [Abstract] [Full Text] [PDF]