Iptakalim modulates ATP-sensitive K+ channels in dopamine neurons from rat substantia nigra pars compacta

Jie Wu, Jun Hu, Yu Ping Chen, Teruko Takeo, Sechiko Suga, Jamie DeChon, Qiang Liu, Ke Chun Yang, Paul A. St. John, Gang Hu, Hai Wang, Makoto Wakui

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)155-164
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number1
DOIs
StatePublished - Oct 2 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Wu, J., Hu, J., Chen, Y. P., Takeo, T., Suga, S., DeChon, J., Liu, Q., Yang, K. C., St. John, P. A., Hu, G., Wang, H., & Wakui, M. (2006). Iptakalim modulates ATP-sensitive K+ channels in dopamine neurons from rat substantia nigra pars compacta. Journal of Pharmacology and Experimental Therapeutics, 319(1), 155-164. https://doi.org/10.1124/jpet.106.106286