Spatiotemporal Coupling of cAMP Transporter to CFTR Chloride Channel Function in the Gut Epithelia

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• 作者：Chunying Li ; Partha C. Krishnamurthy ; Himabindu Penmatsa ; Kevin L. Marrs ; Xue Qing Wang ; Manuela Zaccolo ; Kees Jalink ; Min Li ; Deborah J. Nelson ; John D. Schuetz ; Anjaparav ; a P. Naren
• 关键词：CELLBIO ; HUMDISEASE ; SIGNALING
• 刊名：Cell
• 出版年：2007
• 出版时间：30 November 2007
• 年：2007
• 卷：131
• 期：5
• 页码：940-951
• 全文大小：1492 K

文摘

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.