Intracellular pH modulates the mechanosensitivity of OSCA/TMEM63 ion channels

Mechanosensitive (MS) channels are essential transducers that convert mechanical stimuli into biochemical signals. OSCA/TMEM63 proteins constitute a conserved family that serves as mechanical and osmotic stress sensors, yet the mechanisms by which the chemical microenvironment modulates their gating remain unclear. Here, we identify intracellular pH as a potent and side-specific regulator of OSCA/TMEM63 activity. Using patch-clamp electrophysiology, we demonstrate that OSCA/TMEM63 currents are reversibly tuned by pH: intracellular acidification suppresses channel activity, whereas alkalinization markedly potentiates it. This regulation is mediated by a pronounced shift in the mechanical activation threshold, thereby effectively tuning channel sensitivity. Our findings establish intracellular pH as a conserved modulator of OSCA/TMEM63 mechanosensitivity, providing a mechanistic framework for understanding how the intracellular chemical milieu is coupled to osmo/mechano sensing.