title: Synergy of cAMP and calcium signaling pathways in CFTR regulation.
abstract: Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, leading to defective apical chloride transport. Patients also experience overactivation of inflammatory processes, including increased calcium signaling. Many investigations have described indirect effects of calcium signaling on CFTR or other calcium-activated chloride channels; here, we investigate the direct response of CFTR to calmodulin-mediated calcium signaling. We characterize an interaction between the regulatory region of CFTR and calmodulin, the major calcium signaling molecule, and report protein kinase A (PKA)-independent CFTR activation by calmodulin. We describe the competition between calmodulin binding and PKA phosphorylation and the differential effects of this competition for wild-type CFTR and the major F508del mutant, hinting at potential therapeutic strategies. Evidence of CFTR binding to isolated calmodulin domains/lobes suggests a mechanism for the role of CFTR as a molecular hub. Together, these data provide insights into how loss of active CFTR at the membrane can have additional consequences besides impaired chloride transport.
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Bozoky
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Saumel
authors.initials: S
authors.lastname: Ahmadi
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Tal
authors.initials: T
authors.lastname: Milman
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Tae Hun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Du
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Di Paola
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Stan
authors.initials: S
authors.lastname: Pasyk
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Roman
authors.initials: R
authors.lastname: Pekhletski
authors.affiliation: Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Keller
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bear
authors.affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; forman@sickkids.ca.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Forman-Kay
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008564:Membrane Potentials; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D020218:Response Elements; D015398:Signal Transduction
chemical_list: D002147:Calmodulin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D002118:Calcium
keywords: NMR; calmodulin; cystic fibrosis; membrane potential assay; phosphorylation