Acute Regulation of Na/H Exchanger NHE3 by Adenosine A1 Receptors Is Mediated by Calcineurin Homologous Protein

Sole, Francesca Di; Cerull, Robert; Babich, Victor; Quiñones, Henry; Gisler, Serge M.; Biber, Jürg; Murer, Heini; Burckhardt, Gerhard; Helmle-Kolb, Corinna; Moe, Orson W.

doi:10.1074/jbc.m306838200

Cited by 44 publications

(81 citation statements)

References 68 publications

(115 reference statements)

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“…Screening of Ͼ3 ϫ 10 6 independent clones yielded 4 positive clones containing cDNA encoding calcineurin homologous protein, which was previously shown to interact with NHE3 (22). Six other clones contained cDNA inserts encoding S-adenosylhomocysteine hydrolase-like 1 (AdoHcyL1).…”

Section: Resultsmentioning

confidence: 99%

IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium

Zhang

Chen

2008

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium

Zhang

Chen

2008

Journal of Biological Chemistry

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“…The bait vector was transformed into Saccharomyces cerevisiae (strain L40; genotype MATa trp1 leu2 his3 LYS2::lexA-HIS3 URA3::LexA-LacZ) (57). An adult mouse kidney cDNA library (Matchmaker, Clontech) was screened as previously described (21,25), using NHE3-cyto as bait. Putative positive colonies were identified and isolated by consecutive colony lift, where permeabilized yeast cells transferred onto Whatman filters were overlaid with 0.2 mg/ml 5-bromo-4-chloro-3-indolyl-␤-Dgalacto-pyranoside (X-gal) in 150 mM NaCl, 50 mM Tris·HCl (pH 7.4), and 0.8% agarose (17,19).…”

Section: Methodsmentioning

confidence: 99%

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Bobulescu

Quiñones²,

Gisler³

et al. 2010

American Journal of Physiology-Renal Physiology

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mine is a potent natriuretic paracrine/autocrine hormone that is central for mammalian sodium homeostasis. In the renal proximal tubule, dopamine induces natriuresis partly via inhibition of the sodium/ proton exchanger NHE3. The signal transduction pathways and mechanisms by which dopamine inhibits NHE3 are complex and incompletely understood. This manuscript describes the role of the serine/ threonine protein phosphatase 2A (PP2A) in the regulation of NHE3 by dopamine. The PP2A regulatory subunit B56␦ (coded by the Ppp2r5d gene) directly associates with more than one region of the carboxy-terminal hydrophilic putative cytoplasmic domain of NHE3 (NHE3-cyto), as demonstrated by yeast-two-hybrid, coimmunoprecipitation, blot overlay, and in vitro pull-down assays. Phosphorylated NHE3-cyto is a substrate for purified PP2A in an in vitro dephosphorylation reaction. In cultured renal cells, inhibition of PP2A by either okadaic acid or by overexpression of the simian virus 40 (SV40) small T antigen blocks the ability of dopamine to inhibit NHE3 activity and to reduce surface NHE3 protein. Dopamineinduced NHE3 redistribution is also blocked by okadaic acid ex vivo in rat kidney cortical slices. These studies demonstrate that PP2A is an integral and critical participant in the signal transduction pathway between dopamine receptor activation and NHE3 inhibition. natriuresis; sodium transport; signal transduction THE INTRARENAL AUTOCRINE/PARACRINE dopamine natriuretic system is critical for mammalian sodium homeostasis (5,8,28,29,37,39,47,49,53). The dopamine precursor 3,4-dihydroxy-Lphenylalanine (L-DOPA) is taken up from the glomerular filtrate and plasma into the proximal tubule (48, 50), decarboxylated to dopamine by the action of the cytoplasmic aromatic amino acid decarboxylase (61), and dopamine is extruded into the urinary lumen as well as the interstitial space (43,51,58). Dopamine locally controls multiple aspects of renal function including renal blood flow, glomerular filtration rate, the setting of tubuloglomerular feedback, renin release, and Na ϩ absorption by the renal tubules (5, 37). Quantitatively, the most important mechanism by which dopamine induces natriuresis is direct suppression of Na ϩ absorption by the renal tubular epithelium (9,20,27,40). Inhibition of proximal Na ϩ absorption translates into effective whole kidney natriuresis because downstream of the proximal tubule, dopamine also inhibits Na ϩ absorption in the thick ascending loop of Henle, tubuloglomerular feedback, and Na ϩ transporters in the distal nephron (37). In the proximal tubule, dopamine inhibits the two principal Na ϩ transporters: the apical membrane Na ϩ /H ϩ exchanger NHE3 (7,23,26,33,59,60) and the basolateral Na ϩ -K ϩ -ATPase (4, 12, 13). Inhibition of NHE3 by dopamine involves reduced transport activity and increased endocytosis (7,33,59) and is associated with NHE3 phosphorylation (33, 64). Two PKA phosphorylation sites (serines 552 and 605 in rat NHE3) are necessary but not sufficient for PKA-mediated NHE3 regulation ...

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“…Moreover, CPA-induced control of NHE3 was blocked by adenosine A 1 receptor antagonists (68). The inactivation of NHE3 by adenosine was suggested to involve calcineurin homologous protein-mediated regulation of NHE3 (67). Whether adenosine also exerts a biphasic effect on proximal tubular reabsorption in vivo, as it was shown for angiotensin II (113), remains to be examined.…”

Section: A Proximal Tubulementioning

confidence: 99%

Adenosine and Kidney Function

Vallon

Mühlbauer²,

Oßwald³

2006

Physiological Reviews

395

379

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In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.

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Acute Regulation of Na/H Exchanger NHE3 by Adenosine A1 Receptors Is Mediated by Calcineurin Homologous Protein

Abstract: Adenosine is an autacoid that regulates renal Na

Cited by 44 publications

References 68 publications

IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium

IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Adenosine and Kidney Function

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Acute Regulation of Na/H Exchanger NHE3 by Adenosine A1 Receptors Is Mediated by Calcineurin Homologous Protein

Abstract: Adenosine is an autacoid that regulates renal Na

Cited by 44 publications

References 68 publications

IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium

IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium

Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Adenosine and Kidney Function

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Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A