PT - JOURNAL ARTICLE AU - Jie Wu AU - Jun Hu AU - Yu-Ping Chen AU - Teruko Takeo AU - Sechiko Suga AU - Jamie DeChon AU - Qiang Liu AU - Ke-Chun Yang AU - Paul A. St. John AU - Gang Hu AU - Hai Wang AU - Makoto Wakui TI - Iptakalim Modulates ATP-Sensitive K<sup>+</sup> Channels in Dopamine Neurons from Rat Substantia Nigra Pars Compacta AID - 10.1124/jpet.106.106286 DP - 2006 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 155--164 VI - 319 IP - 1 4099 - http://jpet.aspetjournals.org/content/319/1/155.short 4100 - http://jpet.aspetjournals.org/content/319/1/155.full SO - J Pharmacol Exp Ther2006 Oct 01; 319 AB - Iptakalim, a novel cardiovascular ATP-sensitive K+ (KATP) 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 KATP 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 KATP channel opener (KCO) diazoxide induced neuronal hyperpolarization and abolished action potential firing, but the SUR2B-selective KCO cromakalim exerted little effect, suggesting that functional KATP 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 KATP channels. Furthermore, in human embryonic kidney 293 cells, iptakalim (300-500 μM) closed diazoxide-induced Kir6.2/SUR1 KATP 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 KATP channel opener in rat SNc DA neurons; instead, iptakalim is a pm-KATP channel closer at high concentrations. These effects of iptakalim stimulate further pharmacological investigation and the development of possible therapeutic applications. The American Society for Pharmacology and Experimental Therapeutics