Synergy of cAMP and calcium signaling pathways in CFTR regulation
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 hav...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 11; pp. E2086 - E2095 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
14.03.2017
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| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a chloride channel located in the apical membrane of epithelia cells. The cAMP signaling pathway and protein phosphorylation are known to be primary controlling mechanisms for channel function. In this study, we present an alternative activation pathway that involves calcium-activated calmodulin binding of the intrinsically disordered regulatory (R) region of CFTR. Beyond their potential therapeutic value, these data provide insights into the intersection of calcium signaling with control of ion homeostasis and the ways in which the local CFTR microdomain organizes itself.
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. 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. |
| Author | Kim, Tae Hun Ahmadi, Saumel Milman, Tal Du, Kai Pasyk, Stan Bear, Christine E. Pekhletski, Roman Keller, Jacob P. Forman-Kay, Julie D. Bozoky, Zoltan Di Paola, Michelle |
| Author_xml | – sequence: 1 givenname: Zoltan surname: Bozoky fullname: Bozoky, Zoltan organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 2 givenname: Saumel surname: Ahmadi fullname: Ahmadi, Saumel organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 3 givenname: Tal surname: Milman fullname: Milman, Tal organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 4 givenname: Tae Hun surname: Kim fullname: Kim, Tae Hun organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 5 givenname: Kai surname: Du fullname: Du, Kai organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 6 givenname: Michelle surname: Di Paola fullname: Di Paola, Michelle organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 7 givenname: Stan surname: Pasyk fullname: Pasyk, Stan organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 8 givenname: Roman surname: Pekhletski fullname: Pekhletski, Roman organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 9 givenname: Jacob P. surname: Keller fullname: Keller, Jacob P. organization: Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208 – sequence: 10 givenname: Christine E. surname: Bear fullname: Bear, Christine E. organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada – sequence: 11 givenname: Julie D. surname: Forman-Kay fullname: Forman-Kay, Julie D. organization: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28242698$$D View this record in MEDLINE/PubMed |
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| Keywords | NMR membrane potential assay calmodulin phosphorylation cystic fibrosis |
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| Snippet | Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, leading to defective apical chloride... Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a chloride channel located in the... |
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| SubjectTerms | Binding sites Biological Sciences Calcium Cystic fibrosis Molecular biology Mutation Phosphorylation PNAS Plus Signal transduction |
| Title | Synergy of cAMP and calcium signaling pathways in CFTR regulation |
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