Mechanisms of CFTR regulation by syntaxin 1A and PKA.
Activation of the chloride selective anion channel CFTR is stimulated by cAMP-dependent phosphorylation and is regulated by the target membrane t-SNARE syntaxin 1A. The mechanism by which SNARE proteins modulate CFTR in secretory epithelia is controversial. In addition, controversy exists as to whether PKA activates CFTR-mediated Cl(-) currents (I(CFTR)) by increasing the number of channels in the plasma membrane and/or by stimulating membrane-resident channels. SNARE proteins play a well known role in exocytosis and have recently been implicated in the regulation of ion channels; therefore this investigation sought to resolve two related issues: (a) is PKA activation or SNARE protein modulation of CFTR linked to changes in membrane turnover and (b) does syntaxin 1A modulate CFTR via direct effects on the gating of channels residing in the plasma membrane versus alterations in membrane traffic. Our data demonstrate that syntaxin 1A inhibits CFTR as a result of direct protein-protein interactions that decrease channel open probability (P(o)) and serves as a model for other SNARE protein-ion channel interactions. We also show that PKA activation can enhance membrane trafficking in some epithelial cell types, and this is independent from CFTR activation or syntaxin 1A association.
Chang
Steven Y
SY
Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago Hospitals, 5841 S. Maryland Avenue, MC 6026, Chicago, IL 60637, USA.
Di
Anke
A
Naren
Anjaparavanda P
AP
Palfrey
H Clive
HC
Kirk
Kevin L
KL
Nelson
Deborah J
DJ
D000954:Antigens, Surface / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004553:Electric Conductivity; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000502:physiology; D050827:Syntaxin 1
D000954:Antigens, Surface; C505032:CFTR protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494212:STX1A protein, human; D050827:Syntaxin 1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017868:Cyclic AMP-Dependent Protein Kinases