Store-independent activation of STIM1-ORAI1 by SPCA2 determines the basal CFTR activity in secretory epithelial cells

Cystic fibrosis transmembrane conductance regulator (CFTR) determines epithelial ion secretion, which is fundamental in various organs. The synergy between cyclic AMP (cAMP) and Ca²⁺ signaling fine-tunes CFTR-mediated secretion; however, the organization of such signaling complexes and their physiological impact remained largely unknown. Here, we identified an apical membrane signaling complex consisting of secretory pathway Ca²⁺-ATPase (SPCA2), stromal interaction molecule 1 (STIM1)/calcium release-activated calcium channel protein 1 (ORAI1), adenylyl cyclases, and CFTR. In this complex, SPCA2 facilitates constitutive, store-independent but STIM1-dependent ORAI1-mediated Ca²⁺ influx by activating ORAI1 and promoting STIM1/ORAI1 interaction, which is essential for basal CFTR function. Analysis by super-resolution dSTORM revealed constitutive organization of the proteins in a nanodomain on the apical membrane, which translates local Ca²⁺ increases to cAMP elevation and CFTR activation in unstimulated cells required for ion secretion. The same system operates in the pancreas, airways, and liver. Our findings reveal an essential, self-directing regulatory mechanism of CFTR-mediated ion secretion in secretory epithelial cells, independent from neurohormonal stimuli.