Synergy of cAMP and calcium signaling pathways in CFTR regulation

被引：44

作者：

Bozoky, Zoltan ^{[1
,2
]}

Ahmadi, Saumel ^{[1
,3
]}

Milman, Tal ^{[1
,2
]}

Kim, Tae Hun ^{[1
,2
]}

Du, Kai ^{[1
]}

Di Paola, Michelle ^{[1
,2
]}

Pasyk, Stan ^{[1
]}

Pekhletski, Roman ^{[1
]}

Keller, Jacob P. ^{[4
,5
]}

Bear, Christine E. ^{[1
,2
,3
]}

Forman-Kay, Julie D. ^{[1
,2
]}

机构：

[1] Hosp Sick Children, Res Inst, Mol Struct & Funct, Toronto, ON M5G 0A4, Canada

[2] Univ Toronto, Dept Biochem, Fac Med, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Physiol, Fac Med, Toronto, ON M5S 1A8, Canada

[4] Northwestern Univ, Dept Commun Sci & Disorders, Evanston, IL 60208 USA

[5] Howard Hughes Med Inst, Ashburn, VA 20147 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 11期

基金：

加拿大健康研究院;

关键词：

calmodulin; cystic fibrosis; NMR; phosphorylation; membrane potential assay; CYSTIC-FIBROSIS; CALMODULIN-BINDING; R-DOMAIN; MOLECULAR RECOGNITION; PHOSPHORYLATION SITES; CHLORIDE TRANSPORT; AIRWAY EPITHELIA; FLUID SECRETION; PROTEIN; CA2+;

D O I：

10.1073/pnas.1613546114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, leading to defective apical chloride transport. Patients also experience over-activation 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.

引用

页码：E2086 / E2095

页数：10

共 50 条

[1]

Alzamora R, 2011, METHODS MOL BIOL, V741, P471, DOI 10.1007/978-1-61779-117-8_29

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