Identification of key amino acid residues responsible for internal and external pH sensitivity of Orai1/STIM1 channels

• Published in: Scientific reports Vol. 5; no. 1; p. 16747
• Main Authors: Tsujikawa, Hiroto, Yu, Albert S, Xie, Jia, Yue, Zhichao, Yang, Wenzhong, He, Yanlin, Yue, Lixia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-11-2015; Nature Publishing Group
• Subjects: 13/109; 38/70; 631/378; 631/57; Acidosis; Amino Acid Motifs; Amino Acids; Calcium - metabolism; Calcium channels; Calcium Channels - chemistry; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium influx; Cations; Extracellular Space - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Hydrogen-Ion Concentration; Intracellular; Intracellular Space - metabolism; Membrane Potentials; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; multidisciplinary; Mutation; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; ORAI1 Protein; pH sensors; Physiology; Protons; Residues; Science; STIM1 protein; Stromal Interaction Molecule 1
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep16747

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 (pH
o
) sensitivity, the molecular mechanism for intracellular pH (pH
i
) 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 pH
o
sensitivity when Ca
2+
is the charge carrier. Unexpectedly, we identify that the residue E190 is responsible for pH
o
sensitivity when Na
+
is the charge carrier. Furthermore, the intracellular mutant H155F markedly diminishes the response to acidic and alkaline pH
i
, suggesting that H155 is responsible for pH
i
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.