The Na+/H+ exchange protein (NHE3) functions in transepithelial Na+ absorption and is primarily expressed in the intestinal and renal brush border membrane. NHE3 regulatory factor 1 (NHERF-1) interacts with NHE3 through two PDZ (for PSD-95, Discs-large and ZO-1 homology) domains, which are protein-protein interaction modules that associate with specific carboxy-terminal motifs on target proteins. Also known as EBP50, NHERF-1 facilitates cAMP inhibition of NHE3 to decrease Na+ adsorption. NHERF-1 functions as a scaffold for an essential multiprotein complex of Ezrin and NHE3 for cAMP-mediated phosphorylation and consequent inhibition of NHE3. The amino-terminal PDZ domain regulates the dimerization of NHERF-1 in vivo. G protein-coupled receptor kinase 6A phosphorylates NHERF-1 at Ser 289 via a PDZ domain-mediated interaction. NHERF-2, also known as E3KARP, is a ubiquitously expressed protein which also functions in NHE2 regulation.
