Activation of protein kinase A acutely inhibits and phosphorylates Na/H exchanger NHE-3.

Moe, Orson W.; Amemiya, Morimasa; Yamaji, Yasuyoshi

doi:10.1172/jci118273

Cited by 84 publications

(73 citation statements)

References 57 publications

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“…Although NHE3 is a substrate for PKA (65,66,76), we have not proven that NHE3 phosphorylation by PKA is necessary for DA to decrease surface NHE3. Previous studies have mapped target serines (Ser-552 and Ser-605) on the cytoplasmic domain of rat NHE3 as functionally significant PKA substrates (65,66).…”

Section: Resultsmentioning

confidence: 68%

Dopamine Acutely Stimulates Na+/H+Exchanger (NHE3) Endocytosis via Clathrin-coated Vesicles

Hu¹,

Fan²,

Crowder³

et al. 2001

Journal of Biological Chemistry

138

167

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Extracellular fluid volume and to a certain extent blood pressure in mammals are determined by the balance between sodium intake and renal sodium excretion (1, 2). As regulator of sodium excretion, the intrarenal autocrine-paracrine dopamine (DA) 1 system assumes far greater importance than circulating endocrine or neurogenic dopamine (3-6). DA is produced in the proximal tubule via decarboxylation of its precursor L-dihydroxyphenylalanine derived from the plasma and glomerular filtrate (7-9) and is then secreted into the tubular lumen where it exerts its effects on multiple nephron segments, which cumulates in inhibition of tubular sodium absorption and natriuresis. Renal DA synthesis and excretion are increased by increased dietary salt and an intravenous saline load (10 -13), and blockade of DA synthesis or DA receptor significantly blunts the natriuretic response (14 -18). Quantitatively, the most significant inhibition of sodium transport occurs in the proximal tubule. DA inhibits proximal tubule sodium absorption partially by hemodynamic alterations (19 -22), but the major effect is directly on the tubule epithelium (23-26) via inhibition of two principal sodium transporters: the apical membrane Na ϩ /K ϩ exchanger (NHE3) (27-33) and the basolateral Na ϩ ,K ϩ -ATPase (34 -38). These effects are mediated by the DA receptor where five molecular isoforms (DR 1 -like receptors: DR 1 and DR 5 , and DR 2 -like receptors DR 2 , DR 3 , and DR 4 ) have been identified to date; all five isoforms are known to be present in the renal tubular epithelium (39 -43).Previous studies in isolated apical membrane vesicles have shown that DA inhibits proximal tubule apical membrane Na ϩ /H ϩ exchange activity mainly via DR 1 -like receptors (25-28, 30, 31, 33) through both PKA-dependent and PKA-independent mechanisms (27, 31). The Na ϩ /H ϩ exchanger on the apical membrane of the renal proximal tubule is encoded by NHE3 (44 -46), one of the seven members of the NHE gene family (47). We have shown in opossum kidney (OK) cells that the DA 1 -like and DA 2 -like receptors have synergistic actions on NHE3 activity and that inhibition of NHE3 activity by DA is accompanied by complex changes in NHE3 phosphorylation and dephosphorylation (33). However, the mechanisms by which DA acutely reduces NHE3 activity have not been examined. Redistribution of NHE3 transporters has been shown to mediate regulation of NHE3 activity in intact kidney (48 -54), in cultured renal epithelial cells (55,56), and in transfected fibroblasts (57-64). In addition, although NHE phosphorylation has been associated with changes in NHE3 activity (52,(65)(66)(67)(68), and phosphorylation appears to be functionally important for regulation of NHE3 activity by pharmacologic activators of protein kinases in transfected fibroblasts (65-67), the physiologic significance of NHE3 phosphorylation is still undetermined. In this paper we characterize one mechanism by which DA acutely inhibits NHE3: the internalization of NHE3 secondary to PKA-mediated NHE3 phosphorylatio...

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Section: Resultsmentioning

confidence: 68%

Dopamine Acutely Stimulates Na+/H+Exchanger (NHE3) Endocytosis via Clathrin-coated Vesicles

Hu¹,

Fan²,

Crowder³

et al. 2001

Journal of Biological Chemistry

138

167

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“…Multiple phosphorylation sites were detected, all localized to the region of the cytosolic tail distal to residue 635. Similarly, NHE3 was reported to be phosphorylated in untreated cells, and additional phosphorylation occurred following elevation of cAMP (52).…”

Section: Regulation Of Nhe Activitymentioning

confidence: 83%

Na+/H+ Exchangers of Mammalian Cells

Orlowski¹,

Grinstein²

1997

Journal of Biological Chemistry

550

429

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“…Rabbit polyclonal anti-NHE3 and anti-D 1 receptor antibodies were produced against a synthetic oligopeptide from the amino acid sequence of rat NHE3 (amino acids 633 to 646) 17 or rat D 1 receptor (amino acids 299 to 307) (Research Genetics). The antisera were affinity purified with immunizing peptide or protein A sepharose (Pharmacia).…”

Section: Methodsmentioning

confidence: 99%

Dopamine ₁ Receptor, G _sα , and Na ⁺ -H ⁺ Exchanger Interactions in the Kidney in Hypertension

Li²,

Albrecht³

et al. 2000

Hypertension

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Abstract-The ability of dopamine 1 (D 1 ) receptors to inhibit luminal Na ϩ -H ϩ exchanger (NHE) activity in renal proximal tubules and induce a natriuresis is impaired in spontaneously hypertensive rats (SHR). However, it is not clear whether the defect is at the level of the D 1 receptor, G s␣ , or effector proteins. The coupling of the D 1 receptor to G s␣ and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D 1 receptor, G s␣ , and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5Ј-O-(3-thiotriphosphate) (GTP␥S) decreased NHE activity and increased NHE3 linked with G s␣ similarly in WKY and SHR, indicating normal G s␣ and NHE3 regulation in SHR. However, D 1 agonists increased NHE3 linked with G s␣ in WKY but not in SHR, and the inhibitory effects of D 1 agonists on NHE activity were less in SHR than in WKY. Moreover, GTP␥S enhanced the inhibitory effect of D 1 agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D 1 receptor from G s␣ /NHE3 in SHR. Similar results were obtained with the use of immortalized renal proximal tubule cells from WKY and SHR. We conclude that the defective D 1 receptor function in renal proximal tubules in SHR is proximal to G s␣ /effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D 1 receptor from G proteins remains to be determined. Because the primary structure of the D 1 receptor is not different between normotensive and hypertensive rats, differences in D 1 receptor posttranslational modification are possible. Key Words: dopamine Ⅲ receptors, dopamine Ⅲ G protein Ⅲ rats, inbred SHR R enal dopamine production, dopamine receptors, and dopamine receptor regulation are important in the pathogenesis of hypertension. 1 Dopamine, produced by renal proximal tubules, is an important paracrine/autocrine inhibitor of renal sodium transport under conditions of sodium loading. 1 The inhibition of sodium transport in renal proximal tubules by dopamine is exerted via the Na ϩ -H ϩ exchanger (NHE) at the luminal or brush border membrane (BBM) and via Na ϩ ,K ϩ -ATPase at the basolateral membrane. 1 The major transport of sodium across the luminal membrane of renal proximal tubules is caused by NHE activity. 2 Five of the 6 isoforms of NHE are expressed in the kidney. 3,4 However, the NHE3 isoform predominates in the BBM of rat renal proximal tubules. 2,5 There is an impaired ability of dopamine 1 (D 1) -like receptors to inhibit NHE activity in BBM of the spontaneously hypertensive rat (SHR). 1 The decreased inhibitory effect of D 1 -like receptors on NHE activity in renal proximal tubules and failure to induce a natriuresis cosegregate with hypertension in SHR and normotensive WistarKyoto rat (WKY) crossbreeds. 6 However, it is not clear whether the impaired inhibitory action of D 1 -like receptors on NHE activity is at the receptors, G proteins, signal transducers, or effectors. G proteins can regulate NHE acti...

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Activation of protein kinase A acutely inhibits and phosphorylates Na/H exchanger NHE-3.

Cited by 84 publications

References 57 publications

Dopamine Acutely Stimulates Na+/H+Exchanger (NHE3) Endocytosis via Clathrin-coated Vesicles

Dopamine Acutely Stimulates Na+/H+Exchanger (NHE3) Endocytosis via Clathrin-coated Vesicles

Na+/H+ Exchangers of Mammalian Cells

Dopamine ₁ Receptor, G _sα , and Na ⁺ -H ⁺ Exchanger Interactions in the Kidney in Hypertension

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Activation of protein kinase A acutely inhibits and phosphorylates Na/H exchanger NHE-3.

Cited by 84 publications

References 57 publications

Dopamine Acutely Stimulates Na+/H+Exchanger (NHE3) Endocytosis via Clathrin-coated Vesicles

Dopamine Acutely Stimulates Na+/H+Exchanger (NHE3) Endocytosis via Clathrin-coated Vesicles

Na+/H+ Exchangers of Mammalian Cells

Dopamine 1 Receptor, G sα , and Na + -H + Exchanger Interactions in the Kidney in Hypertension

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Product

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Dopamine ₁ Receptor, G _sα , and Na ⁺ -H ⁺ Exchanger Interactions in the Kidney in Hypertension