title: Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke.
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 focused on the role of extracellular pH in ASIC activation. By contrast, intracellular pH (pHi) has received little attention. This is a significant gap in our 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 vitro and brain ischemia-induced infarct volume in vivo Moreover, we find that the potentiation of ASICs by quinine depends on 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.
authors.affiliation: From the Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon 97239, limin@ohsu.edu.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Li
authors.affiliation: the Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, and.
authors.forename: Tian-Dong
authors.initials: TD
authors.lastname: Leng
authors.affiliation: the Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, 130000 Changchun, China.
authors.forename: Xue-Chao
authors.initials: XC
authors.lastname: Feng
authors.affiliation: the Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, and.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: the Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, and.
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
authors.affiliation: the Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, and zxiong@msm.edu.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006863:Hydrogen-Ion Concentration; D051379:Mice; D011422:Propionates / Q000378:metabolism; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C568267:ASIC1 protein, mouse; C568265:ASIC2 protein, mouse; C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D011422:Propionates
keywords: acid sensing ion channel (ASIC); brain; electrophysiology; ischemia; patch clamp