1. Spatiotemporal Coupling of cAMP Transporter to CFTR Chloride Channel Function in the Gut Epithelia
- Author
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Li, Chunying, Krishnamurthy, Partha C., Penmatsa, Himabindu, Marrs, Kevin L., Wang, Xue Qing, Zaccolo, Manuela, Jalink, Kees, Li, Min, Nelson, Deborah J., Schuetz, John D., and Naren, Anjaparavanda P.
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INTESTINAL diseases , *ION channels , *CYSTIC fibrosis , *GENETIC disorders - Abstract
Summary: 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. [Copyright &y& Elsevier]
- Published
- 2007
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