Stimulation of neuronal KATP channels by cGMP-dependent protein kinase: Involvement of ROS and 5-hydroxydecanoate-sensitive factors in signal transduction

Yongping Chai, Yu-Fung Lin

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The ATP-sensitive potassium (KATP) channel couples intracellular metabolic state to membrane excitability. Recently, we demonstrated that neuronal KATP channels are functionally enhanced by activation of a nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) signaling cascade. In this study, we further investigated the intracellular mechanism underlying PKG stimulation of neuronal KATP channels. By performing single-channel recordings in transfected HEK293 and neuroblastoma SH-SY5Y cells, we found that the increase of Kir6.2/SUR1 (i.e., the neuronal-type KATP) channel currents by PKG activation in cell-attached patches was diminished by 5-hydroxydecanoate (5-HD), an inhibitor of the putative mitochondrial K ATP channel; N-(2-mercaptopropionyl) glycine, a reactive oxygen species (ROS) scavenger, and catalase, a hydrogen peroxide (H2O 2)-decomposing enzyme. These reagents also ablated NO-induced K ATP channel stimulation and prevented the shifts in the single-channel open- and closed-time distributions resulting from PKG activation and NO induction. Bath application of H2O2 reproduced PKG stimulation of Kir6.2/SUR1 but did not activate tetrameric Kir6.2LRKR368/369/ 370/371AAAA channels. Moreover, neither the PKG activator nor exogenous H 2O2 was able to enhance the function of KATP channels in the presence of Ca2+ chelators and calmodulin antagonists, whereas the stimulatory effect of H2O2 was unaffected by 5-HD. Altogether, in this report we provide novel evidence that activation of PKG stimulates neuronal KATP channels by modulating intrinsic channel gating via a 5-HD-sensitive factor(s)/ROS/Ca 2+/calmodulin signaling pathway that requires the presence of the SUR1 subunit. This signaling pathway may contribute to neuroprotection against ischemic injury and regulation of neuronal excitability and neurotransmitter release by modulating the function of neuronal KATP channels.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume298
Issue number4
DOIs
StatePublished - Apr 2010

Keywords

  • Adenosine 5′-triphosphate-sensitive potassium channel
  • Hydrogen peroxide
  • Nitric oxide
  • Patch clamp
  • Single channel

ASJC Scopus subject areas

  • Cell Biology
  • Physiology
  • Medicine(all)

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