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

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 physiol...

Teljes leírás

Elmentve itt :
Bibliográfiai részletek
Szerzők: Kiss Aletta Kata
Varga Árpád
Görög Marietta
Madácsy Tamara
Chung Woo Young
Pallagi Petra
Szabó Viktória
Susánszki Petra
Kúthy-Sutus Enikő
Varga Dániel
Bíró Péter
Sendstad Ingrid Hegnes
Crul Tim
Jójárt Boldizsár
Tél Bálint
Horváth Zsófia
Barnai Szintia
Balázs Anita
Lázár György ifj
Erdélyi Miklós
Muallem Shmuel
Maléth József
Dokumentumtípus: Cikk
Megjelent: 2025
Sorozat:CURRENT BIOLOGY 35 No. 20
Tárgyszavak:
Klinikai orvostan
doi:10.1016/j.cub.2025.09.006

mtmt:36356148
Online Access:http://publicatio.bibl.u-szeged.hu/37852
Leíró adatok
Tartalmi kivonat: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.
Terjedelem/Fizikai jellemzők:25
4970-4987.e7
ISSN:0960-9822

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