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

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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 - 2006

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Dopaminergic Neurons
KATP Channels
Adenosine Triphosphate
Rotenone
Diazoxide
Mitochondrial Membranes
Pars Compacta
N-(1-methylethyl)-1,1,2-trimethylpropylamine
Sulfonylurea Receptors
Cell Membrane
Cromakalim
Rhodamine 123
Physiological Stress
Optical Imaging
Neuroprotective Agents
Ion Channels
Action Potentials
Pharmacology
Staining and Labeling
Kidney

ASJC Scopus subject areas

  • Pharmacology

Cite this

Iptakalim modulates ATP-sensitive K+ channels in dopamine neurons from rat substantia nigra pars compacta. / Wu, Jie; Hu, Jun; Chen, Yu Ping; Takeo, Teruko; Suga, Sechiko; DeChon, Jamie; Liu, Qiang; Yang, Ke Chun; St John, Paul A; Hu, Gang; Wang, Hai; Wakui, Makoto.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 319, No. 1, 2006, p. 155-164.

Research output: Contribution to journalArticle

Wu, J, Hu, J, Chen, YP, Takeo, T, Suga, S, DeChon, J, Liu, Q, Yang, KC, St John, PA, 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, vol. 319, no. 1, pp. 155-164. https://doi.org/10.1124/jpet.106.106286
Wu, Jie ; Hu, Jun ; Chen, Yu Ping ; Takeo, Teruko ; Suga, Sechiko ; DeChon, Jamie ; Liu, Qiang ; Yang, Ke Chun ; St John, Paul A ; Hu, Gang ; Wang, Hai ; Wakui, Makoto. / Iptakalim modulates ATP-sensitive K+ channels in dopamine neurons from rat substantia nigra pars compacta. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 319, No. 1. pp. 155-164.
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AU - Hu, Jun

AU - Chen, Yu Ping

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AU - Suga, Sechiko

AU - DeChon, Jamie

AU - Liu, Qiang

AU - Yang, Ke Chun

AU - St John, Paul A

AU - Hu, Gang

AU - Wang, Hai

AU - Wakui, Makoto

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