Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+
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 p...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58682-w |
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| author | Wei-Yin Lin Woo Young Chung Seonghee Park Ava Movahed Abtahi Benjamin Leblanc Malini Ahuja Shmuel Muallem |
| author_facet | Wei-Yin Lin Woo Young Chung Seonghee Park Ava Movahed Abtahi Benjamin Leblanc Malini Ahuja Shmuel Muallem |
| author_sort | Wei-Yin Lin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a09fc8b025754bdca7c6cc4ff6dc6d18 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-a09fc8b025754bdca7c6cc4ff6dc6d182025-08-20T02:28:04ZengNature PortfolioNature Communications2041-17232025-04-0116112010.1038/s41467-025-58682-wMultiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+Wei-Yin Lin0Woo Young Chung1Seonghee Park2Ava Movahed Abtahi3Benjamin Leblanc4Malini Ahuja5Shmuel Muallem6The Epithelial Signaling and Transport Section and The National Institute of Dental and Craniofacial Research, National Institutes of HealthThe Epithelial Signaling and Transport Section and The National Institute of Dental and Craniofacial Research, National Institutes of HealthDepartment of Physiology, Ewha Womans University College of MedicineThe Epithelial Signaling and Transport Section and The National Institute of Dental and Craniofacial Research, National Institutes of HealthThe Epithelial Signaling and Transport Section and The National Institute of Dental and Craniofacial Research, National Institutes of HealthThe Epithelial Signaling and Transport Section and The National Institute of Dental and Craniofacial Research, National Institutes of HealthThe Epithelial Signaling and Transport Section and The National Institute of Dental and Craniofacial Research, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s41467-025-58682-w |
| spellingShingle | Wei-Yin Lin Woo Young Chung Seonghee Park Ava Movahed Abtahi Benjamin Leblanc Malini Ahuja Shmuel Muallem 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 |
| title | Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+ |
| title_full | Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+ |
| title_fullStr | Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+ |
| title_full_unstemmed | Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+ |
| title_short | Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+ |
| title_sort | multiple camp pka complexes at the stim1 er pm junction specified by e syt1 and e syt2 reciprocally gates ano1 tmem16a via ca2 |
| url | https://doi.org/10.1038/s41467-025-58682-w |
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