{"title":"STIM1 functions as a proton sensor to coordinate cytosolic pH with store-operated calcium entry.","authors":"Yilan Chen, Panpan Liu, Ziyi Zhong, Hanhan Zhang, Aomin Sun, Youjun Wang","doi":"10.1016/j.jbc.2024.107924","DOIUrl":null,"url":null,"abstract":"<p><p>The meticulous regulation of intracellular pH (pH<sub>i</sub>) is crucial for maintaining cellular function and homeostasis, impacting physiological processes such as heart rhythm, cell migration, proliferation, and differentiation. Dysregulation of pH<sub>i</sub> is implicated in various pathologies such as arrhythmias, cancer, and neurodegenerative diseases. Here, we explore the role of STIM1, an ER calcium (Ca<sup>2+</sup>) sensor mediating Store Operated Ca<sup>2+</sup> Entry (SOCE), in sensing pH<sub>i</sub> changes. Our study reveals that STIM1 functions as a sensor for pH<sub>i</sub> changes, independent of its Ca<sup>2+</sup>-binding state. Through comprehensive experimental approaches including confocal microscopy, FRET-based sensors, and mutagenesis, we demonstrate that changes in pH<sub>i</sub> induce conformational alterations in STIM1, thereby modifying its subcellular localization and activity. We identify two conserved histidine within STIM1 essential for sensing pH<sub>i</sub> shifts. Moreover, intracellular alkalization induced by agents such as Angiotensin II or NH<sub>4</sub>Cl enhances STIM1-mediated SOCE, promoting cardiac hypertrophy. These findings reveal a novel facet of STIM1 as a multi-modal stress sensor that coordinates cellular responses to both Ca<sup>2+</sup> and pH fluctuations. This dual functionality underscores its potential as a therapeutic target for diseases associated with pH and Ca<sup>2+</sup> dysregulation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107924"},"PeriodicalIF":4.0000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biological Chemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jbc.2024.107924","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The meticulous regulation of intracellular pH (pHi) is crucial for maintaining cellular function and homeostasis, impacting physiological processes such as heart rhythm, cell migration, proliferation, and differentiation. Dysregulation of pHi is implicated in various pathologies such as arrhythmias, cancer, and neurodegenerative diseases. Here, we explore the role of STIM1, an ER calcium (Ca2+) sensor mediating Store Operated Ca2+ Entry (SOCE), in sensing pHi changes. Our study reveals that STIM1 functions as a sensor for pHi changes, independent of its Ca2+-binding state. Through comprehensive experimental approaches including confocal microscopy, FRET-based sensors, and mutagenesis, we demonstrate that changes in pHi induce conformational alterations in STIM1, thereby modifying its subcellular localization and activity. We identify two conserved histidine within STIM1 essential for sensing pHi shifts. Moreover, intracellular alkalization induced by agents such as Angiotensin II or NH4Cl enhances STIM1-mediated SOCE, promoting cardiac hypertrophy. These findings reveal a novel facet of STIM1 as a multi-modal stress sensor that coordinates cellular responses to both Ca2+ and pH fluctuations. This dual functionality underscores its potential as a therapeutic target for diseases associated with pH and Ca2+ dysregulation.
期刊介绍:
The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.