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1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710; and 2 Department of Medicine, University of Maryland School of Medicine, and Medical Service, Department of Veterans Affairs Medical Center, Baltimore, Maryland 21201
Vectorial ion transport initiated by Na+/H+ exchanger isoform 3 (NHE3) mediates the reabsorption of NaCl and NaHCO3 in renal proximal tubule cells. NHE3 activity is modulated by numerous physiological stimuli. Biochemical and cellular experiments identified Na+/H+ exchanger regulatory factor (NHERF) as a protein cofactor essential for cAMP-mediated inhibition of NHE3 activity. Identification of numerous NHERF targets, including several transmembrane receptors and ion transporters, has broadened the role of this PSD-95/Dlg-1, Drososphila disk large/ZO-1 domain-containing adapter protein in membrane physiology. NHERF also associates with members of the ezrin/radixin/moesin family of actin-binding proteins and thus links NHE3 to the actin cytoskeleton. Formation of this multiprotein complex facilitates NHE3 phosphorylation and hormonal control of Na+/H+ exchange. NHERF also plays a critical role in targeting transport proteins to apical membranes. Moreover, the NHERF signaling complex functions as a regulatory unit to control endocytosis and internal trafficking of membrane proteins. This article reviews the new evidence that implicates NHERF in wider aspects of epithelial membrane biology.
sodium/hydrogen exchanger regulatory factor; apical membrane; ion transport; PSD-95/Dlg/ZO-1 domain; phosphoproteins; actin cytoskeleton
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