title: Regulation of the CFTR chloride channel from humans and sharks.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) in an ATP-dependent channel which mediates cAMP-stimulated chloride secretion by epithelia, particularly those of the pancreas, airways, and intestine. CFTR homologues have been found in all higher vertebrates examined to date and also in some lower vertebrates, although only the human, shark, and Xenopus genes have been heterologously expressed and shown to generate protein kinase A-activated Cl channels. Once phosphorylated, CFTR channels require hydrolyzable nucleotides to be active, but they can be locked in an open burst state when exposed to mixtures of ATP and its hydrolysis-resistant analogue AMP-PNP. This locking requires low-level phosphorylation at unidentified sites that are not among the ten "strong" (dibasic) PKA consensus sequences on CFTR. Mutagenesis of the dibasic PKA sites, which reduces in vitro phosphorylation by > 98%, reduces open probability (Po) by about 50% whilst having no effect on burst duration. Thus, incremental phosphorylation of these sites under normal conditions does not increase Po by slowing down ATP hydrolysis and stabilizing the open burst state, although locking does strictly require low-level phosphorylation at one or more cryptic sites. In addition to serving as a Cl channel, there is compelling evidence that CFTR inhibits the amiloride-sensitive, epithelial sodium channel (ENaC). The mechanism of coupling is not known but most likely involves physical interactions between the channels, perhaps mediated by an intermediate protein that impinges on other transport proteins. CFTR does not function as a conductive channel for ATP; however, extracellular ATP does regulate epithelial channels through activation of P2U purinergic receptors and, after being hydrolyzed extracellularly, through activation of adenosine receptors which elevate cAMP.
authors: Department of Physiology, McGill University, Montréal, Québec, Canada.
authors: J W
authors: JW
authors: Hanrahan
authors: C J
authors: CJ
authors: Mathews
authors: R
authors: R
authors: Grygorczyk
authors: J A
authors: JA
authors: Tabcharani
authors: Z
authors: Z
authors: Grzelczak
authors: X B
authors: XB
authors: Chang
authors: J R
authors: JR
authors: Riordan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012754:Sharks
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D010744:Phosphoric Monoester Hydrolases