Modulation of acid-sensing ion channel 1a by intracellular pH and its role in ischemic stroke

Minghua Li, Tian Dong Leng, Xue Chao Feng, Tao Yang, Roger P. Simon, Zhi Gang Xiong

Research output: Contribution to journalArticle

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Abstract

An important contributor to brain ischemia is known to be extracellular acidosis, which activates acid-sensing ion channels (ASICs), a family of proton-gated sodium channels. Lines of evidence suggest that targeting ASICs may lead to novel therapeutic strategies for stroke. Investigations of the role of ASICs in ischemic brain injury have naturally focusedonthe roleofextracellular pH in ASIC activation. By contrast, intracellular pH (pHi) has received little attention. This is asignificant gap inour understanding because the ASIC response to extracellular pH is modulated by pHi, and activation of ASICs by extracellular protons is paradoxically enhanced by intracellular alkalosis. Our previous studies show that acidosis-induced cell injury in in vitro models is attenuated by intracellular acidification. However, whether pHi affects ischemic brain injury in vivo is completely unknown. Furthermore, whereas ASICs in native neurons are composed of different subunits characterized by distinct electrophysiological/pharmacological properties, the subunit-dependent modulation of ASIC activity by pHi has not been investigated. Using a combination of in vitro and in vivo ischemic brain injury models, electrophysiological, biochemical, and molecular biological approaches, we show that the intracellular alkalizing agent quinine potentiates, whereas the intracellular acidifying agent propionate inhibits, oxygen-glucose deprivation-induced cell injury in vitroand brain ischemiainduced infarct volume in vivo. Moreover, we find that the potentiation of ASICsbyquinine dependson the presence of the ASIC1a, ASIC2a subunits, but not ASIC1b, ASIC3 subunits. Furthermore, we have determined the amino acids in ASIC1a that are involved in the modulation of ASICs by pHi.

Original languageEnglish (US)
Pages (from-to)18370-18383
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number35
DOIs
StatePublished - Aug 26 2016

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ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Molecular Biology
  • Cell Biology

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