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Journal of Cell Science 115, 783-791 (2002)
© 2002 The Company of Biologists Limited

Research Article

Mechanisms of CFTR regulation by syntaxin 1A and PKA

Steven Y. Chang1,*, Anke Di2,*, Anjaparavanda P. Naren3, H. Clive Palfrey2, Kevin L. Kirk3 and Deborah J. Nelson2,{ddagger}

1 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
2 Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, 947 East 58th St, MC 0926, Chicago, IL 60637, USA
3 Department of Physiology and Biophysics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, 1918 University Blvd, MCLM 985, Birmingham, AL 35294, USA

{ddagger} Author for correspondence (e-mail: dnelson{at}drugs.bsd.uchicago.edu )

Accepted 4 November 2001

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 (ICFTR) 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 (Po) 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.

Key words: Membrane capacitance, FM1-43, Exocytosis, Endocytosis, SNARE proteins, Trafficking, Chloride channel, Voltage clamp


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Ion channel regulation by syntaxin 1a (p. 783)

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