title: Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.
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.
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Canada.|Department of Biochemistry, University of Toronto, Toronto, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chin
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Canada.
authors.forename: Maurita
authors.initials: M
authors.lastname: Hung
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Canada. bear@sickkids.ca.|Department of Biochemistry, University of Toronto, Toronto, Canada. bear@sickkids.ca.|Department of Physiology, University of Toronto, Toronto, Canada. bear@sickkids.ca.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bear
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017384:Sequence Deletion / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Channel gating; Cytoskeleton; Interdomain interactions; Modulators; Phosphorylation; Trafficking