Compartmentalized Regulation of CFTR Chloride Channel Function in Apical Epithelia

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is located primarily at the apical plasma membrane of polarized epithelial cells, plays a crucial role in transepithelial fluid homeostasis. Tight regulation of CFTR function is critical, as either hypofunctioning or hyperfunctioning of CFTR activity may result in life-threatening disorders. Accumulating evidence has suggested that the regulation of CFTR channel function is highly compartmentalized, i.e., CFTR function is tightly fine-tuned in localized microdomains, in which CFTR-containing multiprotein complexes play a critical role. A growing number of proteins has been reported to interact directly or indirectly with CFTR, implying that CFTR is coupled functionally and/or physically to a wide variety of interacting partners including ion channels, receptors, transporters, scaffolding proteins, enzyme molecules, signaling molecules, and effectors. In this review article, I summarized the most recent studies that characterize the compartmentalized regulation of CFTR function coupled to some interacting proteins such as receptors (i.e., adenosine receptor, beta adrenergic receptor, and lysophosphatidic acid receptor), transporters (i.e., cAMP efflux pump MRP4), and enzyme molecules (i.e., protein kinases, protein phosphatase, cAMP-specific phosphodiesterases, etc). These compartmentalized and dynamic interactions modulate not only the channel function, but also the localization and processing of CFTR protein within cells.