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Cell. 2007 Nov 30;131(5):940-51.

Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia.

Author information

1
Department of Physiology, The University of Tennessee Health Science Center, 894 Union Avenue, 420 Nash, Memphis, TN 38163, USA.

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized at apical cell membranes and exists in macromolecular complexes with a variety of signaling and transporter molecules. Here, we report that the multidrug resistance protein 4 (MRP4), a cAMP transporter, functionally and physically associates with CFTR. Adenosine-stimulated CFTR-mediated chloride currents are potentiated by MRP4 inhibition, and this potentiation is directly coupled to attenuated cAMP efflux through the apical cAMP transporter. CFTR single-channel recordings and FRET-based intracellular cAMP dynamics suggest that a compartmentalized coupling of cAMP transporter and CFTR occurs via the PDZ scaffolding protein, PDZK1, forming a macromolecular complex at apical surfaces of gut epithelia. Disrupting this complex abrogates the functional coupling of cAMP transporter activity to CFTR function. Mrp4 knockout mice are more prone to CFTR-mediated secretory diarrhea. Our findings have important implications for disorders such as inflammatory bowel disease and secretory diarrhea.

PMID:
18045536
PMCID:
PMC2174212
DOI:
10.1016/j.cell.2007.09.037
[Indexed for MEDLINE]
Free PMC Article

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