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

Kiss, Aletta and Varga, Árpád and Görög, Marietta and Tamara, Madácsy and Chung, Woo Young and Pallagi, Perta and Szabó, Viktória and Susánszki, Petra and Kúthy-Sutus, Enikő and Varga, Dániel and Bíró, Péter and Senstad, Ingrid Hagnes and Crul, Tim and Jójárt, Boldizsár and Tél, Bálint and Horváth, Zsófia and Barnai, Szintia and Balázs, Anita and Lázár, György and Erdélyi, Miklós and Muallem, Shmuel and Maléth, József (2025) Store-independent activation of STIM1-ORAI1 by SPCA2 determines the basal CFTR activity in secretory epithelial cells. CURRENT BIOLOGY. ISSN 0960-9822 (In Press)

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Abstract

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)/ORAI1, adenylyl cy- clases, 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 pro- teins 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.

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