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 (Ca²⁺) sensor mediating Store Operated Ca²⁺ Entry (SOCE), in sensing pH_i changes. Our study reveals that STIM1 functions as a sensor for pH_i changes, independent of its Ca²⁺-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 histidine within STIM1 essential for sensing pH_i 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.