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Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms

Nature volume 390, pages 302–305 (1997)Cite this article

Abstract

The cystic fibrosis gene encodes a cyclic AMP-gated chloride channel (CFTR) that mediates electrolyte transport across the luminal surfaces of a variety of epithelial cells1,2,3,4. The molecular mechanisms that modulate CFTR activity in epithelial tissues are poorly understood. Here we show that CFTR is regulated by an epithelially expressed syntaxin (syntaxin 1A), a membrane protein that also modulates neurosecretion5,6,7 and calcium-channel gating8,9,10,11 in brain. Syntaxin 1A physically interacts with CFTR chloride channels and regulates CFTR-mediated currents both in Xenopus oocytes and in epithelial cells that normally express these proteins. The physical and functional interactions between syntaxin 1A and CFTR are blocked by a syntaxin-binding protein of the Munc18 protein family (also called n-Sec1; refs 12,13,14). Our results indicate that CFTR function in epithelial cells is regulated by an interplay between syntaxin and Munc18 isoforms.

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Figure 1: Expression of syntaxin and Munc18 isoforms in colonic epithelial cells.
Figure 2: CFTR physically interacts with syntaxin 1A.
Figure 3: Syntaxin 1A and Munc18 regulate CFTR-mediated chloride currents in Xenopus oocytes.
Figure 4: Soluble syntaxin 1A cytosolic domain potentiates CFTR-mediated chloride currents in T84 colonic epithelial cells that endogenously express CFTR and membrane-anchored syntaxin 1A.
Figure 5: Figure 5 Botulinum neurotoxin C1 and Munc18a also potentiate CFTR-mediated currents in epithelial cells.

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Acknowledgements

We thank S. Reddy, U. Gopalakrishnan, P. St John and M. N. Shelton for assistance, E. Weber, T. Jilling, T. Elton and D. Abrahamson for advice, and T. Südhof for syntaxin 1A antibody and rat syntaxin 1A cDNA.

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Author notes

  1. Anjaparavanda P. Naren, Deborah J. Nelson and Michael W. Quick: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Biophysics, Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, 35294, Alabama, USA

    Anjaparavanda P. Naren, Biljana Jovov, Dale J. Benos & Kevin L. Kirk

  2. Department of Neurobiology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Michael W. Quick

  3. Departments of Medicine and Neurology, University of Chicago, Chicago, 60037, Illinois, USA

    Deborah J. Nelson & Weiwen Xie

  4. Department of Neuroscience, Kennedy Krieger Institute and The Johns Hopkins University School of Medicine, Baltimore, 21250, Maryland, USA

    Jonathan Pevsner

  5. Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Mark K. Bennett

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  1. Anjaparavanda P. Naren
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Correspondence to Kevin L. Kirk.

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Naren, A., Nelson, D., Xie, W. et al. Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms. Nature 390, 302–305 (1997). https://doi.org/10.1038/36882

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