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Cell Mol Life Sci. 2017 Jan;74(1):57-66. doi: 10.1007/s00018-016-2388-6. Epub 2016 Oct 8.

Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.

Chin S1,2, Hung M1, Bear CE3,4,5.

Author information

1
Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Canada.
2
Department of Biochemistry, University of Toronto, Toronto, Canada.
3
Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Canada. bear@sickkids.ca.
4
Department of Biochemistry, University of Toronto, Toronto, Canada. bear@sickkids.ca.
5
Department of Physiology, University of Toronto, Toronto, Canada. bear@sickkids.ca.

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface. Due to the multiple roles of PKA phosphorylation, there is growing interest in targeting PKA-dependent signaling for rescuing the trafficking and functional defects of F508del-CFTR. This review will discuss the effects of PKA phosphorylation on wild-type CFTR, the consequences of CF mutations on PKA phosphorylation, and the development of therapies that target PKA-mediated signaling.

KEYWORDS:

Channel gating; Cytoskeleton; Interdomain interactions; Modulators; Phosphorylation; Trafficking

PMID:
27722768
DOI:
10.1007/s00018-016-2388-6
[Indexed for MEDLINE]

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