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Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+

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  • Wei-Yin Lin

    (National Institutes of Health)

  • Woo Young Chung

    (National Institutes of Health)

  • Seonghee Park

    (Ewha Womans University College of Medicine)

  • Ava Movahed Abtahi

    (National Institutes of Health)

  • Benjamin Leblanc

    (National Institutes of Health)

  • Malini Ahuja

    (National Institutes of Health)

  • Shmuel Muallem

    (National Institutes of Health)

Abstract

ANO1 plays a crucial role in determining numerous physiological functions, including epithelial secretion, yet its regulatory mechanisms remain incompletely understood. Here, we describe a fundamental dynamic regulation of ANO1 surface expression and Ca2+-dependent gating via the cAMP/PKA pathway at the STIM1 ER/PM junctions. At these junctions, STIM1 assembles AC-AKAP-PKA complexes, while E-Syt1 mediates formation of ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP5-PKA complex, that phosphorylates ANO1 S673, increasing ANO1 Ca2+ affinity. Within these complexes, the Ca2+ and cAMP pathways act synergistically to enhance ANO1 function. By contrast, E-Syt2 dissociates the ANO1-VAPA interaction, forming ANO1-IRBIT-E-Syt2-AC6-AKAP11-PKA complex that phosphorylates ANO1 S221, which markedly reduces ANO1 Ca2+ affinity. The effects of the E-Syts are primarily mediated by their reciprocal regulation of junctional PI(4)P, PI(4,5)P2 and PtdSer. Accordingly, IRBIT deletion in mice impairs receptor-stimulated activation of ANO1 and fluid secretion. These findings should have broad implications for ANO1 roles and functions across various tissues.

Suggested Citation

  • Wei-Yin Lin & Woo Young Chung & Seonghee Park & Ava Movahed Abtahi & Benjamin Leblanc & Malini Ahuja & Shmuel Muallem, 2025. "Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58682-w
    DOI: 10.1038/s41467-025-58682-w
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