title: Identification of key amino acid residues responsible for internal and external pH sensitivity of Orai1/STIM1 channels.
abstract: Changes of intracellular and extracellular pH are involved in a variety of physiological and pathological processes, in which regulation of the Ca(2+) release activated Ca(2+) channel (I CRAC) by pH has been implicated. Ca(2+) entry mediated by I CRAC has been shown to be regulated by acidic or alkaline pH. Whereas several amino acid residues have been shown to contribute to extracellular pH (pHo) sensitivity, the molecular mechanism for intracellular pH (pHi) sensitivity of Orai1/STIM1 is not fully understood. By investigating a series of mutations, we find that the previously identified residue E106 is responsible for pHo sensitivity when Ca(2+) is the charge carrier. Unexpectedly, we identify that the residue E190 is responsible for pHo sensitivity when Na(+) is the charge carrier. Furthermore, the intracellular mutant H155F markedly diminishes the response to acidic and alkaline pHi, suggesting that H155 is responsible for pHi sensitivity of Orai1/STIM1. Our results indicate that, whereas H155 is the intracellular pH sensor of Orai1/STIM1, the molecular mechanism of external pH sensitivity varies depending on the permeant cations. As changes of pH are involved in various physiological/pathological functions, Orai/STIM channels may be an important mediator for various physiological and pathological processes associated with acidosis and alkalinization.
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tsujikawa
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Yu
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Xie
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Yang
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: He
authors.affiliation: Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Yue
mesh_terms: D020816:Amino Acid Motifs; D000596:Amino Acids; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000071740:ORAI1 Protein; D011522:Protons; D000071737:Stromal Interaction Molecule 1
chemical_list: D000596:Amino Acids; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D011522:Protons; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium