TY - JOUR
T1 - Modulation of acid-sensing ion channel 1a by intracellular pH and its role in ischemic stroke
AU - Li, Ming Hua
AU - Leng, Tian Dong
AU - Feng, Xue Chao
AU - Yang, Tao
AU - Simon, Roger P.
AU - Xiong, Zhi Gang
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/8/26
Y1 - 2016/8/26
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M115.713636
DO - 10.1074/jbc.M115.713636
M3 - Article
C2 - 27402850
AN - SCOPUS:84984689022
SN - 0021-9258
VL - 291
SP - 18370
EP - 18383
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -