Compartmentalized crosstalk of CFTR and TMEM16A (ANO1) through EPAC1 and ADCY1 |
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| Institution: | 1. University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, C8, 1749-016 Lisboa, Portugal;2. Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany;3. Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy;1. Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, United States;2. Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, United States;1. Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cardinal Glennon Children''s Medical Center, Saint Louis University School of Medicine, St Louis, MO, USA;2. Department of Pediatrics, Cardinal Glennon Children''s Medical Center, Saint Louis University School of Medicine, St Louis, MO, USA;3. Department of Medicine, Division of Hematology, Stanford University, Stanford, CA, USA;4. Stanford Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA;5. The AHEAD Institute, Saint Louis University School of Medicine, St Louis, MO, USA;6. Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA;7. WNY Pediatric Gastroenterology and Nutrition, DGRD, Buffalo NY, USA;8. Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA;1. Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA;2. Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA;3. Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA;4. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA;1. Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary;2. Center for Translational Medicine and Institute of Pancreatic Diseases, Semmelweis University, 1085 Budapest, Hungary;3. Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation, University of Szeged, 6725 Szeged, Hungary;4. Department of Gastroenterology, Hannover Medical School, 30625 Hannover, Germany;5. Institute of Physiology, Regensburg University, 93040 Regensburg, Germany |
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| Abstract: | Airway epithelial cells express both Ca2+ activated TMEM16A/ANO1 and cAMP activated CFTR anion channels. Previous work suggested a significant crosstalk of intracellular Ca2+ and cAMP signaling pathways, leading to activation of both chloride channels. We demonstrate that in airway epithelial cells, stimulation of purinergic or muscarinic G-protein coupled receptors (GPCRs) activates TMEM16A and CFTR. Additional expression of Gq/11 and phospholipase C coupled GPCRs strongly enhanced the crosstalk between Ca2+- and cAMP-dependent signaling. Knockdown of endogenous GRCRs attenuated crosstalk and functional coupling between TMEM16A and CFTR. The number of receptors did not affect expression or membrane localization of TMEM16A or CFTR, but controlled assembly of the local signalosome. GPCRs translocate Ca2+-sensitive adenylate cyclase type 1 (ADCY1) and exchange protein directly activated by cAMP (EPAC1) to particular plasma membrane domains containing GPCRs, CFTR and TMEM16A, thereby producing compartmentalized Ca2+ and cAMP signals and significant crosstalk. While biosynthesis and membrane trafficking of CFTR requires a functional Golgi apparatus, maturation and membrane trafficking of TMEM16A may occur independent of the Golgi. Because Ca2+ activated TMEM16A currents are only transient, continuous Cl? secretion by airway epithelial cells requires CFTR. The present data also explain why receptor-dependent activation of TMEM16A is more efficient than direct stimulation by Ca2+. |
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