cGMP Inhibition of Na+/H+ Antiporter 3 (NHE3) Requires PDZ Domain Adapter NHERF2, a Broad Specificity Protein Kinase G-anchoring Protein

Cha, Boyoung; Kim, Jae Ho; Hut, Hans; Hogema, Boris M.; Nadarja, Janani; Žižak, Mirza; Cavet, Megan E.; Lee-Kwon, Whaseon; Lohmann, Suzanne M.; Smolenski, Albert; Tse, Chung Ming; Yun, Chris; Jonge, Hugo R. de; Donowitz, Mark

doi:10.1074/jbc.m500505200

Cited by 92 publications

(124 citation statements)

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“…NHERF1 and NHERF2 have been previously shown to contribute to acute NHE3 stimulation and inhibition (3)(4)(5)(6)(7)(8)(9)(10). Recently, two additional PDZ domain containing proteins, termed NHERF3/ PDZK1 and NHERF4/PDZK2/IKEPP, have been demonstrated to possess sequence homology with NHERF1 and NHERF2 (11)(12)(13)(14).…”

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confidence: 99%

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

Zachos¹,

Li²,

Kovbasnjuk³

et al. 2009

Journal of Biological Chemistry

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Elevated intracellularIn normal digestive physiology, the brush border (BB) 2 Na ϩ /H ϩ exchanger, NHE3, mediates the majority of the NaCl and NaHCO 3 absorption in the ileum (1). Sequential inhibition and stimulation of NHE3 occur as part of digestive physiology. Short-term regulation of NHE3 activity is achieved through a variety of factors that affect NHE3 turnover number and/or surface expression and often involve a role for the cytoskeleton and accessory proteins, including the multi-PDZ domain containing proteins, NHERF1 and NHERF2 (1, 2). However, many details of this regulation are not understood.The NHERF (Na ϩ /H ϩ exchanger regulatory factor) family of multi-PDZ domain containing proteins consists of four evolutionarily related members, all of which are expressed in epithelial cells of the mammalian small intestine (2). NHERF1 and NHERF2 have been previously shown to contribute to acute NHE3 stimulation and inhibition (3-10). Recently, two additional PDZ domain containing proteins, termed NHERF3/ PDZK1 and NHERF4/PDZK2/IKEPP, have been demonstrated to possess sequence homology with NHERF1 and NHERF2 (11-14). However, unlike NHERF1 and NHERF2, which are comprised of two tandem PDZ domains flanked by a C-terminal ezrin/radixin/moesin binding domain, NHERF3 and NHERF4 consist of four PDZ domains but no other proteinprotein interacting domains (12). NHERF3 was initially identified by a yeast two-hybrid screen from a human kidney cDNA library using the membrane-associated protein MAP17, as bait (12). NHERF3 is expressed in the brush border of epithelial cells of the kidney proximal tubule and the small intestine (12). NHERF3 associates with and, in a few cases, has been shown to regulate the activity of multiple apical membrane ion transporters including the cystic fibrosis transmembrane regulator (CFTR), urate anion exchanger 1 (URAT1), sodium-phosphate cotransporter type IIa (NaP i IIa), proton-coupled peptide transporter (PEPT2), and organic cation/carnitine cotransporter (OCTN2) (15-19). Furthermore, NHERF3 directly binds the C terminus of NHE3 (20). Recent studies have begun evaluating the effect of NHERF3 on mouse intestinal Na ϩ and Cl Ϫ transport. Basal electroneutral sodium absorption was decreased by Ͼ40% in the NHERF3 null mouse jejunum (21) and by Ͼ80% in the colon (22). In addition, Cinar * This work was supported, in whole or in part, by National Institutes of Health Grants R01-DK26523, R01-DK61765, PO1-DK72084, K01-DK080930, and R24-DK64388 (The Hopkins Basic Research Digestive Diseases Development Core Center) from the NIDDK. This work was also supported by Grant T32-DK07632 from The Hopkins Center for Epithelial Disorders.

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confidence: 99%

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

Zachos¹,

Li²,

Kovbasnjuk³

et al. 2009

Journal of Biological Chemistry

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“…18 NHERF2 is needed for the cGMP-mediated inhibition of NHE3 by the cGMP kinase II (Prkg2). 19 In contrast to AQP2 and ENaC, PKA mediates an inhibition of NHE3. 20 To investigate possible transplant-related changes in the expression of these effectors and transporters important for renal function, we have performed gene expression analysis using microarrays.…”

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confidence: 99%

Acute Rejection Modulates Gene Expression in the Collecting Duct

Edemir

Reuter²,

Borgulya³

et al. 2008

Journal of the American Society of Nephrology

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Kidney transplantation, especially when associated with acute rejection, leads to changes in the expression of many genes, including those encoding solute transporters and water channels. In a rat model of acute rejection after allogeneic renal transplantation, impaired renal function, increased urine volume, and increased fractional excretion of sodium were observed. Gene array analysis revealed that these findings were associated with significant downregulation of water channels (aquaporin-1, -2, -3, and -4) and transporters of sodium, glucose, urea, and other solutes. In addition, changes in expression of various receptors, kinases, and phosphatases that modulate the expression or activity of renal transport systems were observed. Syngeneic transplantation or treatment with cyclosporine A following allogeneic transplantation did not impair graft function but did lead to the downregulation of aquaporin-1, -3, and -4 and several solute transporters. However, expression of aquaporin-2 and the epithelial sodium channel did not change, suggesting that the downregulation of these transporters following allogeneic transplantation is rejection-dependent. In conclusion, changes in gene expression may explain the impaired handling of solute and water after allogeneic transplantation, especially during acute rejection. Treatment with cyclosporine A improves the regulation of solute and water by preventing the downregulation of aquaporin-2 and epithelial sodium channel, even though many other transporter genes remain downregulated. Renal transplantation (TX) in humans is often accompanied by increased transport capacities of the graft and disturbances in salt and water homeostasis. 1-3 Half-life of grafts with normal function after TX is 11.5 yr compared with 7.2 yr for those with impaired renal function. 4 A better understanding of the underlying cellular and molecular mechanisms leading to such changes may help to increase longterm graft survival.Previously, using an allogeneic rat renal TX (aTX) model, we have demonstrated acute changes in expression and function of several transporters and receptors after aTX. 5,6 For example, the expression of Na ϩ /H ϩ -exchanger-3 (NHE3), aquaporin-2 (AQP2), and the epithelial Na ϩ channel (ENaC) were downregulated at the protein and mRNA level. Major transporters for water and Na ϩ reabsorption in the collecting duct (CD) are ENaC and AQP2. 7 The expression and activity of AQP2 are regulated by the antidiuretic hormone (vasopressin, AVP) via the G-protein coupled AVP-2 receptor (V2R). 8 The binding of AVP to the V2R leads to the activation of the G-protein Gs, followed by activation of adenylate cyclase (AC), increased cyclic adenosine monophosphate (cAMP) levels, activation of protein kinase A (PKA), and finally phosphorylation of AQP2 9 and translocation to the

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“…NHERF2 was reported to act as a protein kinase G-anchoring protein for cyclic GMP kinase II in the cGMP-mediated regulation of sodiumehydrogen exchanger 3 (NHE3). 28 In addition, cyclic GMP kinase II cGKII is known to mediate cGMP-responsive activation of CFTR. It is possible that NHERF2 exhibits a dual role in assembling CFTR and iNOS at the plasma membrane, as well as functioning as a protein kinase G-anchoring…”

Section: Discussionmentioning

confidence: 99%

“…cAMPdriven inhibition of NHE3 can be mediated via NHERF1, NHERF2, and NHERF3 (PDZK1), whereas cGMP-mediated inhibition was found to specifically require NHERF2. 28,57 NO was found to inhibit NHE3 function by the NO-cGMP pathway, but without account for the effect of inducible NO under inflammation conditions for NHE3 regulation. 40,58 In another study, NHE3 expression was found to be unaltered in cytokine-induced inflammation in interleukin-10edeficient mice marked by up-regulated iNOS levels.…”

Section: Cftr-inos Signaling Complexmentioning

confidence: 96%

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

Arora

Sinha

Zhang

et al. 2015

The American Journal of Pathology

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Ulcerative colitis (UC) belongs to inflammatory bowel disorders, a group of gastrointestinal disorders that can produce serious recurring diarrhea in affected patients. The mechanism for UC-and inflammatory bowel disorder-associated diarrhea is not well understood. The cystic fibrosis transmembraneconductance regulator (CFTR) chloride channel plays an important role in fluid and water transport across the intestinal mucosa. CFTR channel function is regulated in a compartmentalized manner through the formation of CFTR-containing macromolecular complexes at the plasma membrane. In this study, we demonstrate the involvement of a novel macromolecular signaling pathway that causes diarrhea in UC. We found that a nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), is overexpressed under the plasma membrane and generates compartmentalized cGMP in gut epithelia in UC. The scaffolding protein Na þ /H þ exchanger regulatory factor 2 (NHERF2) bridges iNOS with CFTR, forming CFTR-NHERF2-iNOS macromolecular complexes that potentiate CFTR channel function via the nitric oxide-cGMP pathway under inflammatory conditions both in vitro and in vivo. Potential disruption of these complexes in Nherf2 À/À mice may render them more resistant to CFTR-mediated secretory diarrhea than Nherf2 þ/þ mice in murine colitis models. Our study provides insight into the mechanism of pathophysiologic occurrence of diarrhea in UC and suggests that targeting CFTR and CFTR-containing macromolecular complexes will ameliorate diarrheal symptoms and improve conditions associated with inflammatory bowel disorders. (Am J Pathol 2015 http://dx

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cGMP Inhibition of Na+/H+ Antiporter 3 (NHE3) Requires PDZ Domain Adapter NHERF2, a Broad Specificity Protein Kinase G-anchoring Protein

Cited by 92 publications

References 46 publications

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

Acute Rejection Modulates Gene Expression in the Collecting Duct

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

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