Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3)

Ambühl, Patrice M.; Yang, Xiaojing; Peng, Yan; Preisig, Patricia A.; Moe, Orson W.; Alpern, Robert J.

doi:10.1172/jci2913

Cited by 45 publications

(44 citation statements)

References 21 publications

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“…The best-characterized mechanism of NHE3 up-regulation is recruitment to the plasma membrane (22,23). The data show that this is also the mechanism by which Na ϩ -glucose cotransport activates NHE3.…”

Section: Discussionmentioning

confidence: 89%

“…We considered NHE3 phosphorylation as a potential regulatory mechanism (21), but, although documented, the role of phosphorylation in NHE3 regulation remains to be established. We also considered trafficking of NHE3 between intracellular vesicles and the apical membrane, which has been described as a mechanism of acute NHE3 up-regulation (22,23). To explore this possibility, we measured surface NHE3 before and after initiation of Na ϩ -glucose cotransport.…”

Section: Translocation Of Nhe3 To the Apical Membrane Is Associated Wmentioning

confidence: 99%

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Ezrin regulates NHE3 translocation and activation after Na ⁺ -glucose cotransport

Zhao

Shiue

Palkon

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Initiation of Na ؉ -glucose cotransport in intestinal epithelial cells leads to activation of the apical Na ؉ -H ؉ exchanger NHE3 and subsequent increases in cytoplasmic pH (pH i). This process requires activation of p38 mitogen-activated protein (MAP) kinase, but additional signaling intermediates have not been identified. One candidate is the cytoskeletal linker protein ezrin, which interacts with NHE3 via specific regulatory proteins. The data show that initiation of Na ؉ -glucose cotransport resulted in rapid increases in both apical membrane-associated NHE3 and cytoskeletal-associated ezrin and occurred in parallel with ezrin phosphorylation at threonine 567. Phosphorylation at this site is known to activate ezrin and increase its association with actin. Consistent with a central role for ezrin activation in this NHE3 regulation, an Nterminal dominant negative ezrin construct inhibited both NHE3 recruitment and pH i increases after Na ؉ -glucose cotransport. Ezrin phosphorylation occurred in parallel with p38 MAP kinase activation, and the latter proceeded normally in cells expressing dominant negative ezrin. In contrast, inhibition of p38 MAP kinase prevented increases in ezrin phosphorylation after initiation of Na ؉ -glucose cotransport. Thus, ezrin phosphorylation after Na ؉ -glucose cotransport requires p38 MAP kinase activity, but p38 MAP kinase activation does not require ezrin function. These data describe a specific role for ezrin in the coordinate regulation of Na ؉ -glucose cotransport and Na ؉ -H ؉ exchange. Intact ezrin function is necessary for NHE3 recruitment to the apical membrane and NHE3-dependent pH i increases triggered by Na ؉ -glucose cotransport. The data also define a pathway of p38 MAP kinase-dependent ezrin activation.

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Section: Discussionmentioning

confidence: 89%

Section: Translocation Of Nhe3 To the Apical Membrane Is Associated Wmentioning

confidence: 99%

Ezrin regulates NHE3 translocation and activation after Na ⁺ -glucose cotransport

Zhao

Shiue

Palkon

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…We have previously shown that the activation of NHE3 in response to chronic acid incubation requires the synergistic effect of hydrocortisone (5). To test for glucocorticoid dependence, we examined the interaction between insulin and hydrocortisone.…”

Section: Insulin Increases Namentioning

confidence: 99%

Insulin activates Na⁺/H⁺exchanger 3: biphasic response and glucocorticoid dependence

Klisic

Hu²,

Nief

et al. 2002

American Journal of Physiology-Renal Physiology

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165

123

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Insulin is an important regulator of renal salt and water excretion, and hyperinsulinemia has been implicated to play a role in hypertension. One of the target proteins of insulin action in the kidney is Na+/H+ exchanger 3 (NHE3), a principal Na+ transporter responsible for salt absorption in the mammalian proximal tubule. The molecular mechanisms involved in activation of NHE3 by insulin have not been studied so far. In opossum kidney (OK) cells, insulin increased Na+/H+exchange activity in a time- and concentration-dependent manner. This effect is due to activation of NHE3 as it persisted after pharmacological inhibition of NHE1 and NHE2. In the early phase of stimulation (2–12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, enhanced NHE3 activity was accompanied by an increase in total and cell surface NHE3 protein and NHE3 mRNA abundance. All the effects of insulin on NHE3 activity, protein, and mRNA were amplified in the presence of hydrocortisone. These results suggest that insulin stimulates renal tubular NHE3 activity via a biphasic mechanism involving posttranslational factors and an increase in NHE3 gene expression and the effects are dependent on the permissive action of hydrocortisone.

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“…The phosphoenolpyruvate carboxykinase (PEPCK) probe was synthesized from a PstI/PstI PEPCK fragment by random hexamer priming using [a-32 P]-dCTP. PEPCK mRNA abundance was quantified by image analysis and normalized for loading using an 18S rRNA oligonucleotide probe synthesized as described elsewhere (15).…”

Section: Figurementioning

confidence: 99%

Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis

Laghmani¹,

Preisig²,

Moe³

et al. 2001

J. Clin. Invest.

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Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3)

Cited by 45 publications

References 21 publications

Ezrin regulates NHE3 translocation and activation after Na ⁺ -glucose cotransport

Ezrin regulates NHE3 translocation and activation after Na ⁺ -glucose cotransport

Insulin activates Na⁺/H⁺exchanger 3: biphasic response and glucocorticoid dependence

Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis

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Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3)

Cited by 45 publications

References 21 publications

Ezrin regulates NHE3 translocation and activation after Na + -glucose cotransport

Ezrin regulates NHE3 translocation and activation after Na + -glucose cotransport

Insulin activates Na+/H+exchanger 3: biphasic response and glucocorticoid dependence

Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis

Contact Info

Product

Resources

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Ezrin regulates NHE3 translocation and activation after Na ⁺ -glucose cotransport

Ezrin regulates NHE3 translocation and activation after Na ⁺ -glucose cotransport

Insulin activates Na⁺/H⁺exchanger 3: biphasic response and glucocorticoid dependence