Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Na(+)/H(+) exchanger regulatory factor (NHERF) and NHERF2 are PDZ motif proteins that mediate the inhibitory effect of cAMP on Na(+)/H(+) exchanger 3 (NHE3) by facilitating the formation of a multiprotein signaling complex. With the use of antibodies specific for NHERF and NHERF2, immunocytochemical analysis of rat kidney was undertaken to determine the nephron distribution of both proteins and their colocalization with other transporters and with ezrin. NHERF was most abundant in apical membrane of proximal tubule cells, where it colocalized with ezrin and NHE3. NHERF2 was detected in the glomerulus and in other renal vascular structures. In addition, NHERF2 was strongly expressed in collecting duct principal cells, where it colocalized with ROMK. These results indicate a striking difference in the nephron distribution of NHERF and NHERF2 and suggests NHERF is most likely to be the relevant biological regulator of NHE3 in the proximal tubule, while NHERF2 may interact with ROMK or other targets in the collecting duct. The finding that NHERF isoforms occur in different cell types suggests that NHERF and NHERF2 may subserve different functions in the kidney.
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PMID:Differential renal distribution of NHERF isoforms and their colocalization with NHE3, ezrin, and ROMK. 1112 91

Biochemical and cellular experiments in fibroblasts have established the requirement for a member of the PDZ motif Na(+)/H(+) exchanger regulatory factor family of proteins (NHERF and NHERF2) in cAMP-mediated phosphorylation and inhibition of NHE3 activity. NHERF interacts with the actin cytoskeleton through the scaffolding protein ezrin to target a multiprotein signal complex to the plasma membrane. Recent experiments have focused on elements of this model. First, using specific antibodies, NHERF was identified in the renal proximal tubule, where it colocalized with ezrin and NHE3. NHERF2 was seen in glomeruli, the renal vasculature, and collecting duct cells, where it colocalized with ROMK. This distinct nephron localization suggests different physiologic roles for NHERF and NHERF2. Second, the signal-complex model of protein kinase A regulation of NHE3 developed in fibroblasts has been extended to epithelial cells by the development of a dominant-negative opossum kidney cell line expressing an ezrin binding domain-deficient truncation of NHERF. Preliminary studies indicate that these cells have normal basal Na+/H+ exchanger activity but a blunted inhibitory response to cAMP. Third, biochemical, biophysical, and cell experiments have indicated that NHERF binds to itself in a head-to-head configuration, raising the possibility that dimerization may alter the availability of active NHERF. The potential role of the NHERF proteins in the kidney has been expanded by recent studies indicating their involvement in the membrane targeting, trafficking, sorting, and regulation of a range of other transporters, receptors, and signaling proteins. NHERF and related PDZ-containing proteins may serve as adapters for regulation of renal transporters.
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PMID:Acute regulation of NHE3 by protein kinase A requires a multiprotein signal complex. 1147 25

Sodium-hydrogen exchanger regulatory factor-1 and -2 (NHERF-1 and NHERF-2) are adaptor proteins that regulate renal electrolyte transport and interact with the platelet-derived growth factor receptors (PDGFR). The distribution of the NHERF proteins and PDGFR was studied in normal human kidneys and in renal transplant rejection using immunocytochemistry. In normal kidneys, NHERF-1 was detected in proximal tubules. NHERF-2 was detected in glomeruli, peritubular capillaries, and collecting duct principal cells. NHERF-2 was also weakly detected in the proximal tubule. PDGFR-beta was detected in glomeruli but not in tubules while PDGFR-alpha was detected in renal tubules and minimally in glomeruli. Acute and chronic transplant rejection was associated with increased expression of PDGFR-alpha in tubules and expression in the glomeruli. PDGFR-beta expression in the glomeruli was increased in transplant rejection and became detectable in tubules. Expression of NHERF-1 and NHERF-2 was not different in the patient groups. These results indicate that in contrast to the rat, both NHERF isoforms are detected in the human proximal tubule. In renal transplant rejection, there is increased expression of both PDGFR subtypes consistent with a role for PDGF in injury or repair.
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PMID:Expression of NHERF-1, NHERF-2, PDGFR-alpha, and PDGFR-beta in normal human kidneys and in renal transplant rejection. 1286 27