Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alpha and beta subunits of Na-K-ATPase are up-regulated by hypertonicity in inner-medullary collecting duct cells adapted to survive in hypertonic conditions. We examined the regulation of the gamma subunit by hypertonicity. Although cultured inner-medullary collecting duct cells lacked the gamma subunits, both variants gamma(a) and gamma(b) were expressed in cells adapted to 600 and 900 mosmol/KgH(2)O. This expression was reversible with a half-time of 17.2 +/- 0.5 h. The message of the gamma subunit was absent in isotonic conditions and increased with higher tonicity in adapted cells. In acute experiments the appearance of the gamma subunit was found to be both time-dependent (> or =24 h) and osmolality-dependent (> or =500 mosmol/KgH(2)O). No induction was noted with urea and only minimal induction with mannitol. Increasing concentrations of the phosphatidylinositol 3-kinase inhibitor LY294002 resulted in a dose-dependent decrement in the expression of the gamma subunit with total abolition at 10 microM. This was associated with a decrease in cell viability as <20% survived the treatment with 10 microM of LY294002. Neither inhibition of extracellular response kinase nor p38 mitogen-activated protein kinase inhibited osmotic induction of the gamma subunit. In contrast, cells transfected with a dominant negative c-Jun N-terminal kinase 2-APF construct displayed complete inhibition of the gamma subunit. Such cells have accelerated loss of viability in hypertonic conditions. This study describes the regulation of the gamma subunit of Na-K-ATPase by hypertonicity. This regulation is transcriptionally regulated and involves signaling mediated by phosphatidylinositol 3-kinase and c-Jun N-terminal kinase 2 pathways.
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PMID:The expression of the gamma subunit of Na-K-ATPase is regulated by osmolality via C-terminal Jun kinase and phosphatidylinositol 3-kinase-dependent mechanisms. 1168 20

We studied the molecular events set into motion by stimulation of D(1)-like receptors downstream of Na(+)-K(+)-ATPase, while measuring apical-to-basal ouabain-sensitive, amphotericin B-induced increases in short-circuit current in opossum kidney (OK) cells. The D(1)-like receptor agonist SKF-38393 decreased Na(+)-K(+)-ATPase activity (IC(50), 130 nM). This effect was prevented by the D(1)-like receptor antagonist SKF-83566, overnight cholera toxin treatment, the protein kinase A (PKA) antagonist H-89, or the PKC antagonist chelerythrine, but not the mitogen-activated PK inhibitor PD-098059 or phosphatidylinositol 3-kinase inhibitors wortmannin and LY-294002. Dibutyryl cAMP (DBcAMP) and phorbol 12,13-dibutyrate (PDBu) both effectively reduced Na(+)-K(+)-ATPase activity. PKA downregulation abolished the inhibitory effects of SKF-38393 and DBcAMP but not those of PDBu. PKC downregulation abolished inhibition by PDBu, SKF-38393, and DBcAMP. The phospholipase C (PLC) inhibitor U-73122 prevented inhibition by SKF-38393 and DBcAMP. However, DBcAMP increased PLC activity. Although OK cells express both G(s)alpha and G(q/11)alpha proteins, D(1)-like receptors are coupled to G(s)alpha proteins only, as evidenced by studies in cells treated overnight with specific antibodies raised against G(s)alpha and G(q/11)alpha proteins. We conclude that PLC and Na(+)-K(+)-ATPase are effector proteins for PKA and PKC, respectively, after stimulation of D(1)-like receptors coupled to G(s)alpha proteins, in a sequence of events that begins with adenylyl cyclase-PKA system activation followed by PLC-PKC system activation.
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PMID:Role of cAMP-PKA-PLC signaling cascade on dopamine-induced PKC-mediated inhibition of renal Na(+)-K(+)-ATPase activity. 1199 25

Clathrin-dependent endocytosis of Na(+),K(+)-ATPase in response to dopamine regulates its catalytic activity in intact cells. Because fission of clathrin-coated pits requires dynamin, we examined the mechanisms by which dopamine receptor signals promote dynamin-2 recruitment and assembly at the site of Na(+),K(+)-ATPase endocytosis. Western blotting revealed that dopamine increased the association of dynamin-2 with the plasma membrane and with phosphatidylinositol 3-kinase. Dopamine inhibited Na(+),K(+)-ATPase activity in OK cells and in those overexpressing wild type dynamin-2 but not in cells expressing a dominant-negative mutant. Dephosphorylation of dynamin is important for its assembly. Dopamine increased protein phosphatase 2A activity and dephosphorylated dynamin-2. In cells expressing a dominant-negative mutant of protein phosphatase 2A, dopamine failed to dephosphorylate dynamin-2 and to reduce Na(+),K(+)-ATPase activity. Dynamin-2 is phosphorylated at Ser(848), and expression of the S848A mutant significantly blocked the inhibitory effect of dopamine. These results demonstrate a distinct signaling network originating from the dopamine receptor that regulates the state of dynamin-2 phosphorylation and that promotes its location (by interaction with phosphatidylinositol 3-kinase) at the site of Na(+),K(+)-ATPase endocytosis.
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PMID:Relevance of dopamine signals anchoring dynamin-2 to the plasma membrane during Na+,K+-ATPase endocytosis. 1220 83

Glycoprotein (GP) VI is a critical platelet collagen receptor, yet the steps involved in GPVI-mediated platelet activation remain incompletely understood. Because activation of Rap1, an abundant small guanosine triphosphatase (GTPase) in platelets, contributes to integrin alpha(IIb)beta(3) activation, we asked whether and how GPVI signaling activates Rap1 in platelets. Here we show that platelet Rap1 is robustly activated upon addition of convulxin, a GPVI-specific agonist. Using a reconstituted system in RBL-2H3 cells, we found that GPVI-mediated Rap1 activation is dependent on FcRgamma but independent of another platelet collagen receptor, alpha(2)beta(1). Interestingly, GPVI-mediated Rap1 activation in human platelets is largely dependent on adenosine diphosphate (ADP) signaling through the P2Y(12) and not the P2Y(1) receptor. However, experiments with specific ADP receptor antagonists and platelets from knockout mice deficient in P2Y(1) or the P2Y(12)-associated G-protein, Galphai(2), indicate that human and murine platelets also have a significant P2Y(12)-independent component of GPVI-mediated Rap1 activation. The P2Y(12)-independent component is dependent on phosphatidylinositol 3-kinase and is augmented by epinephrine-mediated signaling. P2Y(12)-dependent and -independent components are also observed in GPVI-mediated platelet aggregation, further supporting a role for Rap1 in aggregation. These results define mechanisms of GPVI-mediated platelet activation and implicate Rap1 as a key signaling protein in GPVI-induced platelet signaling.
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PMID:Identification of P2Y12-dependent and -independent mechanisms of glycoprotein VI-mediated Rap1 activation in platelets. 1239 17

Human neural stem cells (NSCs) grown in culture responded to extracellularly applied adenosine triphosphate (ATP), and the rate of proliferation increased as shown by immunocytochemical and RT-PCR analysis. Activation of P2 purinoceptors by ATP is coupled to the release of intracellular calcium ([Ca(2+)](i)) from thapsigargin-sensitive intracellular stores. ATP-induced proliferation was blocked by thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase. Neither EGTA, a calcium chelator, nor caffeine had any effect on ATP-induced [Ca(2+)](i) increases. Multiblot kinase analysis, by which activation of 24 different kinases could be determined, showed that application of ATP to NSCs predominantly activated p70 ribosomal protein S6 kinase (p70 S6 kinase). As well, rapamycin, a p70 S6 kinase inhibitor, blocked the ATP-mediated proliferative response in NSCs. After outlining a role for p70 S6 kinase in ATP-mediated NSC proliferation, we examined the possibility that phosphatidylinositol 3-kinase (PI3-kinase) acts upstream of p70 S6 kinase. The application of wortmannin, a PI3-kinase inhibitor, decreased both ATP-mediated p70 S6 kinase activation and NSC proliferation. From these results, we conclude that ATP application to NSCs induces release of Ca(2+) from intracellular Ca(2+) stores and that this increase in intracellular Ca(2+) in turn promotes NSC proliferation. The increase in NSC proliferation observed following ATP application can also be mediated by PI3-kinase-dependent p70 S6 kinase activation.
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PMID:Adenosine triphosphate induces proliferation of human neural stem cells: Role of calcium and p70 ribosomal protein S6 kinase. 1269 2

Vacuolar H(+)-ATPase (V-ATPase) binds microfilaments, and that interaction may be mediated by an actin binding domain in subunit B of the enzyme. To test for possible physiologic functions of the actin binding activity of V-ATPase, early responses of resorbing osteoclasts to inhibition of phosphatidylinositol 3-kinase activity by wortmannin and LY294002 were examined. Rapid co-localization between V-ATPase and F-actin was demonstrated by immunocytochemistry, and corresponding association between V-ATPase and F-actin in immunoprecipitations and pelleting assays was detected. This response was reversed as osteoclasts recovered resorptive activity after inhibitors were removed. By expressing and characterizing fusion proteins containing segments of the actin-binding amino-terminal regions of the B subunits of V-ATPase, we mapped the actin-binding site to a 44-amino acid domain. An 11-amino acid segment with a sequence similar to the actin-binding site of human profilin I was detected within this region. 13-Mers containing these profilin-like segments bound actin in fluorescent anisotropy studies and competed with profilin for binding to actin. Using site-directed mutagenesis, the 11-amino acid profilin-like actin-binding motifs (amino acids 49-59 of B1 and 55-65 of B2) were replaced with an 11-amino acid spacer with a sequence based on the homologous sequence from subunit B of Pyrococcus horikoshii, an organism that lacks an actin cytoskeleton. These substitutions eliminated the actin-binding activity of the B subunit fusion proteins. In summary, binding between V-ATPase and F-actin in osteoclasts occurs in response to blocking phosphatidylinositol 3-kinase activity. This response was fully reversible. The actin binding activities of the B subunits of V-ATPase required 11-amino acid actin-binding motifs that are similar in sequence to the actin-binding site of mammalian profilin I.
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PMID:Vacuolar H+-ATPase binding to microfilaments: regulation in response to phosphatidylinositol 3-kinase activity and detailed characterization of the actin-binding site in subunit B. 1466 73

Insulin stimulates Na(+),K(+)-ATPase activity and induces translocation of Na(+),K(+)-ATPase molecules to the plasma membrane in skeletal muscle. We determined the molecular mechanism by which insulin regulates Na(+),K(+)-ATPase in differentiated primary human skeletal muscle cells (HSMCs). Insulin action on Na(+),K(+)-ATPase was dependent on ERK1/2 in HSMCs. Sequence analysis of Na(+),K(+)-ATPase alpha-subunits revealed several potential ERK phosphorylation sites. Insulin increased ouabain-sensitive (86)Rb(+) uptake and [(3)H]ouabain binding in intact cells. Insulin also increased phosphorylation and plasma membrane content of the Na(+),K(+)-ATPase alpha(1)- and alpha(2)-subunits. Insulin-stimulated Na(+),K(+)-ATPase activation, phosphorylation, and translocation of alpha-subunits to the plasma membrane were abolished by 20 microm PD98059, which is an inhibitor of MEK1/2, an upstream kinase of ERK1/2. Furthermore, inhibitors of phosphatidylinositol 3-kinase (100 nm wortmannin) and protein kinase C (10 microm GF109203X) had similar effects. Notably, insulin-stimulated ERK1/2 phosphorylation was abolished by wortmannin and GF109203X in HSMCs. Insulin also stimulated phosphorylation of alpha(1)- and alpha(2)-subunits on Thr-Pro amino acid motifs, which form specific ERK substrates. Furthermore, recombinant ERK1 and -2 kinases were able to phosphorylate alpha-subunit of purified human Na(+),K(+)-ATPase in vitro. In conclusion, insulin stimulates Na(+),K(+)-ATPase activity and translocation to plasma membrane in HSMCs via phosphorylation of the alpha-subunits by ERK1/2 mitogen-activated protein kinase.
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PMID:ERK1/2 mediates insulin stimulation of Na(+),K(+)-ATPase by phosphorylation of the alpha-subunit in human skeletal muscle cells. 1506 82

We have investigated the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine protein kinase B (Akt) in mediating vascular smooth muscle cells (VSMC) sodium pump (Na+, K(+)-ATPase) regulatory interactions between insulin-like growth factor-1 (IGF-1) and angiotensin II (Ang II). Treatment with IGF-1 (100 nM) for 30 min or Ang II (100 nM) for 10 min increased sodium pump activity. Pretreatment with Ang II for 10 min, abolished IGF-1 increased sodium pump activity. Given separately for 6 h, Ang II and IGF-1 stimulated alpha1 mRNA accumulation. Phosphorylation on Ser473 of Akt was increased after treatment with both IGF-1 and Ang II. Pretreatment with 100 nM of PI3K inhibitor Wortmannin (WT) for 30 min decreased: IGF-1 and Ang II-stimulated pump activity, phosphorylation of Akt and PI3K protein expression. Pretreatment with Ang II attenuated IGF-1-stimulated sodium pump activity, phosphorylation of Akt and PI3K protein expression. IGF-1 increased the association between IRS-1 and p85, and Ang II as well as PI3K inhibition decreased this IGF-1 effect. These results suggest that Ang II, which increases pump activity alone, reduces the IGF-1 stimulation of sodium pump activity by attenuating PI3K/Akt signaling. These results implicate PI3K/Akt pathways in Ang II/IGF-1 regulation of the sodium pump in VSMC.
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PMID:Ang II attenuates IGF-1-stimulated Na+, K(+)-ATPase activity via PI3K/Akt pathway in vascular smooth muscle cells. 1513 35

The vacuolar H(+)-ATPase (V-ATPase) acidifies compartments of the vacuolar system of eukaryotic cells. In renal epithelial cells, it resides on the plasma membrane and is essential for bicarbonate transport and acid-base homeostasis. The factors that regulate the H(+)-ATPase remain largely unknown. The present study examines the effect of glucose on H(+)-ATPase activity in the pig kidney epithelial cell line LLC-PK(1). Cellular pH was measured by performing ratiometric fluorescence microscopy using the pH-sensitive indicator BCECF-AM. Intracellular acidification was induced with NH(3)/NH(4)(+) prepulse, and rates of intracellular pH (pH(i)) recovery (after in situ calibration) were determined by the slopes of linear regression lines during the first 3 min of recovery. The solutions contained 1 microM ethylisopropylamiloride and were K(+) free to eliminate Na(+)/H(+) exchange and H(+)-K(+)-ATPase activity. After NH(3)/NH(4)(+)-induced acidification, LLC-PK(1) cells had a significant pH(i) recovery rate that was inhibited entirely by 100 nM of the V-ATPase inhibitor concanamycin A. Acute removal of glucose from medium markedly reduced V-ATPase-dependent pH(i) recovery activity. Readdition of glucose induced concentration-dependent reactivation of V-ATPase pH(i) recovery activity within 2 min. Glucose replacement produced no significant change in cell ATP or ADP content. H(+)-ATPase activity was completely inhibited by the glycolytic inhibitor 2-deoxy-d-glucose (20 mM) but only partially inhibited by the mitochondrial electron transport inhibitor antimycin A (20 microM). The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (500 nM) abolished glucose activation of V-ATPase, and activity was restored after wortmannin removal. Glucose activates V-ATPase activity in kidney epithelial cells through the glycolytic pathway by a signaling pathway that requires PI3K activity. These findings represent an entirely new physiological effect of glucose, linking it to cellular proton secretion and vacuolar acidification.
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PMID:Glucose activates H(+)-ATPase in kidney epithelial cells. 1518 20

We examined the effect of leptin on renal function and renal Na(+),K(+)-ATPase and ouabain-sensitive H(+),K(+)-ATPase activities in the rat. Leptin was infused under general anaesthesia into the abdominal aorta proximally to the renal arteries. Leptin infused at doses of 1 and 10 microg/kg/min increased urine output by 40% and 140%, respectively. Urinary Na(+) excretion increased in rats receiving leptin at doses of 0.1, 1, and 10 microg/kg/min by 57.6%, 124.2% and 163.6%, respectively. Leptin had no effect on creatinine clearance, potassium excretion and phosphate excretion. Na(+),K(+)-ATPase activity in the renal medulla of rats treated with 1 and 10 microg/kg/min leptin was lower than in control animals by 25.5% and 33.2%, respectively. In contrast, cortical Na(+),K(+)-ATPase as well as either cortical or medullary ouabain-sensitive H(+),K(+)-ATPase activities did not differ between leptin-treated and control animals. The effect of leptin on Na(+),K(+)-ATPase activity was abolished by actin depolymerizing agents, cytochalazin D and latrunculin B, and by phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002. These results indicate that: 1). natriuretic effect of leptin is mediated, at least in part, by decrease in renal medullary Na(+),K(+)-ATPase activity, 2). inhibition of medullary Na(+),K(+)-ATPase by leptin is mediated by PI3K and requires integrity of actin cytoskeleton.
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PMID:Leptin decreases renal medullary Na(+), K(+)-ATPase activity through phosphatidylinositol 3-kinase dependent mechanism. 1521 61


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