Signal complex regulation of renal transport proteins: NHERF and regulation of NHE3 by PKA

The activity of the sodium/hydrogen exchanger 3 (NHE3) isoform of the sodiu m/hydrogen exchanger in the brush-border membrane of the renal proximal tub ule is tightly regulated. Recent biochemical and cellular experiments have established the essential requirement for a new class of regulatory factors , sodium/hydrogen exchanger regulatory factor (NHERF) and NHERF-like protei ns, in cAMP-mediated inhibition of NHE3 activity. NHERF is the first PSD95/ Dlg/ ZO-1 (PDZ) motif-containing protein localized to apical membranes and appears to facilitate cAMP-dependent protein kinase A (PKA) phosphorylation of NHE3 by interacting with the cytoskeleton to target a multiprotein comp lex to the brush-border membrane. Other recent experiments have indicated t hat NHERF also regulates the activity of other renal transport proteins, su ggesting that the signal complex model of signal transduction in the kidney may be more common than presently appreciated. This article reviews studie s on the regulation of NHE3 by NHERF, PKA, and ezrin and introduces the con cept of regulation of renal transporters by signal complexes. Although not the primary focus of this review, recent studies have indicated a role for NHERF in membrane targeting, trafficking, and sorting of transporters, rece ptors, and signaling proteins. Thus NHERF and related PDZ-containing protei ns appear to be essential adapters for regulation of renal transporters in the mammalian kidney that maintain salt and water balance.