Store-independent activation of STIM1-ORAI1 by SPCA2 determines the basal CFTR activity in secretory epithelial cells
Year: 2025
Type: article
Abstract: Cystic fibrosis transmembrane conductance regulator (CFTR) determines epithelial ion secretion, which is fundamental in various organs. The synergy between cyclic AMP (cAMP) and Ca 2+ 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 Ca 2+ -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 Ca 2+ 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 Ca 2+ 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.
Source: Current Biology
Authors: Aletta Kata Kiss, Árpád Varga, Marietta Görög, Tamara Madácsy, Woo Young Chung, Petra Pallagi, Viktória Szabó, Petra Susánszki, Enikő Kúthy-Sutus, Dániel Varga, Péter Bíró, Ingrid Hegnes Sendstad, Tim Crul, Boldizsár Jójárt, Bálint Tél, Zsófia Horváth, Szintia Barnai, Anita Balázs, György Lázár, Miklós Erdélyi, Shmuel Muallem, József Maléth
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $7,030
OpenAlex ID: W4414573798