STIM1 functions as a proton sensor to coordinate cytosolic pH with store-operated calcium entry.

The meticulous regulation of intracellular pH (pH(i)) is crucial for maintaining cellular function and homeostasis, impacting physiological processes such as heart rhythm, cell migration, proliferation, and differentiation. Dysregulation of pH(i) is implicated in various pathologies such as arrhythmias, cancer, and neurodegenerative diseases. Here, we explore the role of STIM1, an ER calcium (Ca(2+)) sensor mediating Store Operated Ca(2+) Entry (SOCE), in sensing pH(i) changes. Our study reveals that STIM1 functions as a sensor for pH(i) changes, independent of its Ca(2+)-binding state. Through comprehensive experimental approaches including confocal microscopy, FRET-based sensors, and mutagenesis, we demonstrate that changes in pH(i) induce conformational alterations in STIM1, thereby modifying its subcellular localization and activity. We identify two conserved histidines within STIM1 essential for sensing pH(i) shifts. Moreover, intracellular alkalization induced by agents such as Angiotensin II or NH(4)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(2+) and pH fluctuations. This dual functionality underscores its potential as a therapeutic target for diseases associated with pH and Ca(2+) dysregulation.