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 inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 11; pp. E2086 - E2095
Main Authors Bozoky, Zoltan, Ahmadi, Saumel, Milman, Tal, Kim, Tae Hun, Du, Kai, Di Paola, Michelle, Pasyk, Stan, Pekhletski, Roman, Keller, Jacob P., Bear, Christine E., Forman-Kay, Julie D.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 14.03.2017
SeriesPNAS Plus
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Summary: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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1Deceased October 15, 2016.
Edited by G. Marius Clore, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, and approved January 30, 2017 (received for review August 16, 2016)
2Present address: Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147.
Author contributions: Z.B., S.A., J.P.K., C.E.B., and J.D.F.-K. designed research; Z.B., S.A., T.M., T.H.K., K.D., M.D.P., S.P., R.P., and J.P.K. performed research; Z.B., S.A., T.M., T.H.K., M.D.P., R.P., C.E.B., and J.D.F.-K. analyzed data; and Z.B. and J.D.F.-K. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1613546114