Overexpression of csk inhibits acid-induced activation of NHE-3.

Yamaji, Yasuyoshi; Amemiya, Morimasa; Cano, Adriana; Preisig, Patricia A.; Miller, R. Tyler; Moe, Orson W.; Alpern, Robert J.

doi:10.1073/pnas.92.14.6274

Cited by 50 publications

(42 citation statements)

References 37 publications

(38 reference statements)

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“…Those similarities provide evidence to suggest that ERK may be a direct proximal component of an NHE regulatory pathway [5,6]. There is a growing awareness that tyrosine phosphorylation cycles are critical in regulating NHE activities in a number of cell types [6][7][8][9][10], as has also been shown for ERK [11]. Other studies have demonstrated that NHE and ERK activities are modulated by overlapping upstream enzymes, including phosphoinositide 3h-kinase (PI-3K), phospholipase Cγ, and PKC [12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Garnovskaya

Mukhin

Raymond

1998

Biochemical Journal

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These experiments tested the hypothesis that signalling elements involved in the activation of the extracellular signal-regulated protein kinase (ERK) mediate rapid activation of sodium-proton exchange (NHE) in fibroblasts when both signals are initiated by a single G protein-coupled receptor, the 5-HT "A receptor. Similarities between the two processes were comparable concentration-response curves and time-courses, and overlapping sensitivity to some pharmacological inhibitors of tyrosine kinases (staurosporine and genistein), and phosphoinositide 3h-kinase (wortmannin and LY204002). Activation of NHE was much more sensitive to the phosphatidylcholine-specific phospholipase inhibitor (D609) than was ERK. Neither pathway was sensitive

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Section: Introductionmentioning

confidence: 99%

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Garnovskaya

Mukhin

Raymond

1998

Biochemical Journal

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“…Mouse embryos lacking csk exhibit increased c-Src, Fyn, and Lyn activity and increased levels of tyrosine protein phosphorylation (38). Overexpression of wild-type Csk suppresses endogenous c-Src activity (39) and, in opossum kidney cells, blocks acid-induced activation of Na ϩ /H ϩ antiporter, a process associated with p60 c-src activation (40). Fig.…”

Section: C-src In G␤␥ Subunit-mediated Map Kinase Regulationmentioning

confidence: 99%

Role of c-Src Tyrosine Kinase in G Protein-coupled Receptorand Gβγ Subunit-mediated Activation of Mitogen-activated Protein Kinases

Luttrell

Hawes

Biesen

et al. 1996

Journal of Biological Chemistry

505

426

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Many receptors that couple to heterotrimeric G proteins have been shown to mediate the rapid activation of MAP 1 kinases. Among these are receptors for several substances either present in the general circulation, released as neurotransmitters, or produced locally by vascular endothelium or activated platelets. These include catecholamines, acetylcholine, pituitary glycopeptide hormones, adenosine, angiotensins, bombesin, endothelins, LPA, and ␣-thrombin (1). Receptors for these substances, activated in response to systemic or locally generated ligands, may in turn play significant roles in the endocrine or paracrine regulation of cell proliferation.Heterogeneity exists in the mechanisms whereby G proteincoupled receptors activate MAP kinases. Depending upon receptor and cell type, MAP kinase activation may be mediated by pertussis toxin-sensitive or -insensitive G proteins and be either PKC-or Ras-dependent. In COS-7 cells, for example, activation of MAP kinase via the pertussis toxin-insensitive, Gq-coupled, ␣1B adrenergic and M1 muscarinic acetylcholine receptors is significantly inhibited by PKC depletion but insensitive to expression of a dominant-negative mutant of Ras. In contrast, activation of MAP kinase via the pertussis toxinsensitive Gi-coupled ␣2A adrenergic and M2 muscarinic acetylcholine receptors is PKC-independent but requires Ras activation and is sensitive to inhibitors of tyrosine protein kinases (2). Similarly, LPA, a potent stimulator of mitogenesis in quiescent fibroblasts that signals via a G protein-coupled receptor coupling to both pertussis toxin-sensitive and -insensitive G proteins (3-5), activates MAP kinase via a pertussis toxin-sensitive pathway involving Ras and Raf activation (6, 7). LPA-mediated MAP kinase activation is sensitive to tyrosine kinase inhibitors (7, 8) but independent of its effects on phosphatidylinositol hydrolysis and its ability to inhibit adenylyl cyclase (4,8). In COS-7 cells, Ras-dependent MAP kinase activation via ␣2A adrenergic (9), M2 muscarinic acetylcholine, D2 dopamine, and A1 adenosine receptors (10) is mediated largely by G␤␥ subunits derived from pertussis toxin-sensitive G proteins. Indeed, overexpression of G␤␥ subunits, but not constitutively activated G␣i1 or G␣i2 mutants, is sufficient to activate MAP kinase (9 -11) in these cells.

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“…Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity. [59][60][61][62] Downstream from c-Src is endothelin-1 (ET-1) production and ET-1/ETB mediates acid stimulation of NHE3 involving exocytic insertion of NHE3 into the apical membrane. This process requires an intact cytoskeleton, 65 and is associated with NHE3 phosphorylation.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity. [59][60][61][62] Downstream from c-Src is endothelin-1 (ET-1) production and secretion by the proximal tubule. 53,63 The mechanism by which c-Src stimulates ET-1 secretion is not yet known.…”

Section: Adaptation To Metabolic Acidosismentioning

confidence: 99%

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

Bobulescu

Moe

2006

Seminars in Nephrology

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The kidney plays key roles in extracellular fluid pH homeostasis by reclaiming bicarbonate (HCO 3 − ) filtered at the glomerulus and generating the consumed HCO 3 − by secreting protons (H + ) into the urine (renal acidification). Sodium-proton exchangers (NHEs) are ubiquitous transmembrane proteins mediating the countertransport of Na + and H + across lipid bilayers. In mammals, NHEs participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as in transepithelial ion transport. Five of the 10 isoforms (NHE1-4 and NHE8) are expressed at the plasma membrane of renal epithelial cells. The best-studied isoform for acid-base homeostasis is NHE3, which mediates both HCO 3 − absorption and H + excretion in the renal tubule. This article reviews some important aspects of NHEs in the kidney, with special emphasis on the role of renal NHE3 in the maintenance of acid-base balance.Keywords sodium/hydrogen exchange; renal acidification; bicarbonate absorption The free hydrogen ion (H + ) concentration in body fluids is regulated exquisitely around 40 nmol/L (pH 7.40) whereas H + flux through the body greatly exceeds this magnitude. In a 70-kg human being at a basal state, normal metabolic and dietary acid production rate is about 50 to 70 mmoles/d and respiratory volatile acid production at the basal state is around 15,000 mmoles/d, with peak production at maximal exercise reaching 200 mmoles/min. The flux of H + through the organism over 24 hours is 8 orders of magnitude greater than the total pool of free H + in total body water (<2 μmoles). This remarkable homeostatic feat is accomplished by concerted efforts of extracellular and intracellular buffers, highly efficient ventilatory responses, metabolic functions of the liver, and renal ammoniagenic and solute transport mechanisms. For excretion of nonvolatile acid and base loads, the kidney assumes the pivotal role.A filtration-reabsorption nephron bears an exorbitant burden of having to reclaim a vast amount of valuable solutes indiscriminately dispensed in the filtrate; one of which of course is the approximately 4,000 mmoles of bicarbonate (HCO 3 − ) per day. The luminal acid disequilibrium pH implies that the predominant mode of HCO 3 − absorption involves H + secretion, although a small concomitant degree of direct HCO 3 − reabsorption cannot be excluded. 1 Two points are noteworthy. First, complete reclamation of the approximately 4,000 mmoles of filtered HCO 3 − forestalls a physiologic disaster but does not lead to net acid secretion. Further elaboration of H + into the urine is necessary. Second, whether the organism is catering to the The era of phenomenologic analysis was supplemented by gene-and protein-specific reagents when the first mammalian NHE was cloned by Sardet et al. 7 The relationship between mammalian NHE genetic sequence and those from a multitude of organisms is shown in Fig 2. Na + /H + exchange across lipid bilayers and proteins that sustain this function are universal in prokaryotic, animal, and...

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Overexpression of csk inhibits acid-induced activation of NHE-3.

Abstract: Opossum kidney OKP cells express an apical membrane Na+/H+ antiporter that is encoded by NHE-3 (for Na+/H+ exchanger 3) and is similar in many respects to the renal proximal tubule apical membrane Na+/H+ antiporter.

Cited by 50 publications

References 37 publications

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

Role of c-Src Tyrosine Kinase in G Protein-coupled Receptorand Gβγ Subunit-mediated Activation of Mitogen-activated Protein Kinases

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

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