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)

1. DARPP-32 is a phosphoprotein regulated by dopamine and cAMP. In its phosphorylated form it acts as an inhibitor of protein phosphatase-1, thereby regulating the phosphorylation state of phosphoproteins in the basal ganglia. 2. In the kidney, DARPP-32 has been detected in the medullary thick ascending limb of Henle (mTAL) and, to a lesser degree, in the proximal convoluted tubule by means of immunohistochemistry and in situ hybridization. 3. In single microdissected tubules of rat kidney, Na+, K(+)-ATPase activity, measured as ouabain-sensitive ATP hydrolysis, has been shown to be inhibited to the same degree by the DA1 agonist fenoldopam, cAMP and a synthesized and phosphorylated DARPP-32 peptide, D32(8-38). 4. It is concluded that the DA1 receptor-mediated inhibition of Na+ transport in the mTAL by dopamine occurs via cAMP accumulation and the phosphoprotein, DARPP-32.
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PMID:Control of electrolyte transport in the kidney through a dopamine- and cAMP-regulated phosphoprotein, DARPP-32. 132 Nov 55

DARPP-32, a dopamine- and adenosine 3',5'-cyclic monophosphate (cAMP)-regulated inhibitor of protein phosphatase-1, is highly colocalized with neuronal and nonneuronal D1-type receptors. DARPP-32 concentration is enriched in the renal outer medulla and in the medium-size spiny neurons of the brain. In the ascending limb of the loop of Henle, DARPP-32 is phosphorylated following stimulation by dopamine and other first messengers, and in this form inhibits the activity of the Na(+)-K(+)-adenosinetriphosphatase pump. For functional analysis of the DARPP-32 promoter in the kidney, we characterized the murine gene. There are two groups of transcription start sites utilized in the brain, but the proximal set appears to be preferentially used in the kidney. In four of four lines of mice carrying a DARPP-32/lacZ transgene with 2.1 kb of 5'-flanking DNA, adult kidney lacZ transgene expression mimicked that of endogenous DARPP-32. There was no ectopic expression in peripheral organs. We conclude that the sequences necessary for direction of DARPP-32 expression to the medullary thick ascending limb are contained within this 2.1-kb fragment.
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PMID:DARPP-32 promoter directs transgene expression to renal thick ascending limb of loop of Henle. 748 43

DARPP-32 is a dopamine- and cAMP-regulated inhibitor of protein phosphatase-1 (PP-1). Dopamine and DARPP-32 regulate sodium reabsorption in renal tubules by inhibiting the activity of Na+,K(+)-ATPase. We here report the pre- and postnatal distributions of DARPP-32 in the kidney as demonstrated by immunoblotting and immunohistochemistry. With immunoblotting we examined the abundance of DARPP-32 and the functionally similar but more widespread inhibitor of PP-1, inhibitor-1 (I-1). We compared their relative abundance in the renal cortex, renal medulla and neostriatum from the brain, where DARPP-32 is greatly enriched. DARPP-32 levels in the adult rat were fourfold higher in the neostriatum than in the renal medulla and 13-fold higher than in the renal cortex. I-1 levels were approximately the same in the neostriatum and in the renal medulla and 2.5-fold higher in neostriatum than in the renal cortex. Between postnatal day 10 (PN10) and 40 (PN40) DARPP-32 abundance increased 1.3-fold in the neostriatum, 1.4-fold in the renal cortex and sixfold in the medulla. The abundance of I-1 did not increase in the striatum from PN10 to PN40 but increased 1.5-fold in the renal cortex and threefold in the renal medulla. Thus, during the time of maturation of tubular transport function, the levels of both PP-1 inhibitors increased in the kidney, the largest increase being found in the renal medulla. With immunohistochemistry strong DARPP-32-like-immunoreactivity (DARPP-32-LI) was detected in the ureteral buds from gestational day 18 and up to postnatal day 8 when nephrogenesis was completed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Distribution of dopamine- and cAMP-dependent phosphoprotein (DARPP-32) in the developing and mature kidney. 823 Oct 21

Na+, K+-ATPase contributes to the high potassium concentration in the endolymph and the resulting endocochlear potential, which are both essential for the function of the sensory part of the inner ear. Na+, K+-ATPase is present in the stria vascularis and it has lately been suggested that its activity is hormonally regulated. The intracellular signalling system for hormonal short-term regulation of Na+, K+-ATPase activity by phosphorylation in renal tubular cells has been well described. In this study, the presence of the intracellular components of this phosphorylation system in the stria vascularis from guinea-pig has been investigated with immunoblotting. The concentrations found were related to those in renal medullary tissue or the corpus striatum. Protein kinase C was present with isoforms alpha, delta and zeta in the stria vascularis. Calcium- and calmodulin-dependent protein kinase II and protein phosphatase-1 isoforms alpha and gamma were found in the stria vascularis. Protein phosphatase-2B, on the other hand, could not be detected. I-1, an inhibitor of protein phosphatase activity, was present, whereas the phosphatase inhibitor dopamine- and cAMP-regulated phosphoprotein (DARPP-32), was not present in the stria vascularis. These results demonstrate that several intracellular components of the phosphorylation/dephosphorylation system are present in the stria vascularis, and suggest that hormonal short-term regulation of Na+, K+-ATPase activity is also possible in the stria vascularis.
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PMID:Protein kinase and protein phosphatase presence in the stria vascularis. 904 45

In this study, we examined the potential role of serine/threonine protein phosphatase-1 (PP-1) and PP-2A in the mechanism of Na+/K+-ATPase activation by insulin in the rat skeletal muscle cell line L6. Incubation of L6 cells with insulin caused a time- and dose-dependent stimulation of ouabain-sensitive plasma membrane Na+/K+-ATPase activity. Pretreatment with okadaic acid (OA; 0.1-1 microM) or calyculin A (1 microM) blocked insulin's effect on Na+/K+-ATPase activation. Low concentrations of OA that specifically inhibit PP-2A were ineffective. Immunoprecipitation of the enzyme from 32P-labeled cells with an antibody directed against the alpha-1 subunit of the enzyme revealed a 60% decrease in 110-kDa protein phosphorylation in insulin-treated cells. The presence of calyculin A blocked insulin-mediated dephosphorylation of Na+/K+-ATPase, whereas low concentrations of OA were ineffective. To further confirm the role of PP-1, we used L6 cell lines that overexpress the glycogen/SR-associated regulatory subunit of PP-1, PP-1G. Overexpression of PP-1G resulted in a 3-fold increase in insulin-stimulated PP-1 catalytic activity. This was accompanied by a 30% increase in basal Na+/K+-ATPase activity and a >2-fold increase in insulin's effect on pump activity. Inhibition of phosphatidylinositol-3 kinase with wortmannin blocked insulin-stimulated PP-1 activation as well as the dephosphorylation and activation of Na+/K+-ATPase. We conclude that insulin regulates the activity of Na+/K+-ATPase by promoting dephosphorylation of the alpha subunit via an insulin-stimulated PP-1 and that phosphatidylinositol-3 kinase-generated signals may mediate insulin activation of PP-1 and Na+/K+-ATPase.
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PMID:Role of serine/threonine protein phosphatases in insulin regulation of Na+/K+-ATPase activity in cultured rat skeletal muscle cells. 929 6

H/K-ATPase preparations (the G1 membrane) from pig stomach contain both kinases and phosphatases and show reversible phosphorylation of Tyr(7), Tyr(10), and Ser(27) residues of the alpha-chain of H/K-ATPase. The Tyr-kinase is sensitive to genistein and quercetin and recognized by anti-c-Src antibody. The Ser-kinase is dependent on Ca(2)(+) (K(0.5) = 0.9 microM), sensitive to a PKC inhibitor, and recognized by antibodies against PKCalpha and PKCbetaII. The addition of 3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonic acid (CHAPS) caused a dramatic increase in the phosphorylation of added synthetic copolymer substrates and permitted the phosphorylation of maltose-binding proteins fused with the N-terminal domain of alpha-chains. The phosphotyrosine phosphatase was inhibited by vanadate. The phosphoserine phosphatase was inhibited by okadaic acid and by inhibitor-2. The presence of protein phosphatase-1 was immunologically detected. Column chromatographic separation of CHAPS-solubilized G1 membrane and others indicate the apparent molecular weight of the Src-kinase to be approximately 60 kDa, the PKCalpha and/or PKCbII to be approximately 80 kDa, the Tyr-phosphatase to be 200 kDa, and PP-1 to be approximately 35 kDa. These data show that these membrane-bound enzyme systems are in sufficiently close proximity to be responsible for reversible phosphorylation of Tyr(7), Tyr(10), and Ser(27) of the catalytic subunit of membrane H/K-ATPase in parietal cells, the physiological role of which is unknown.
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PMID:Membrane enzyme systems responsible for the Ca(2+)-dependent phosphorylation of Ser(27), the independent phosphorylation of Tyr(10) and Tyr(7), and the dephosphorylation of these phosphorylated residues in the alpha-chain of H/K-ATPase. 1078 91

Inhibitor-1 and DARPP-32 (dopamine and cAMP-regulated phosphoprotein, Mr 32 kDa) are each phosphorylated by cAMP-dependent protein kinase, resulting in their conversion to potent inhibitors of protein phosphatase-1. Protein phosphatase-1 is involved in the regulation of Na(+) reabsorption from renal tubule by modulating the activity of Na(+),K(+)-ATPase. In this study, we have investigated the regulation of inhibitor-1 and DARPP-32 phosphorylation in slices of renal medulla. Activation of cAMP-dependent protein kinase by forskolin and 8-bromo-cAMP increased the level of phosphorylated inhibitor-1. Okadaic acid (1 microM), used to inhibit protein phosphatase-2A, increased the level of phosphorylated inhibitor-1, but cyclosporin A had no effect. DARPP-32, like inhibitor-1, was phosphorylated by cAMP-dependent protein kinase and dephosphorylated only by protein phosphatase-2A. These data demonstrate that the phosphorylation of inhibitor-1 and DARPP-32 is regulated by the balance of phosphorylation by cAMP-dependent protein kinase and dephosphorylation by protein phosphatase-2A in renal medulla. Furthermore, the phosphorylation step is regulated by pharmacological stimuli such as activation of beta(1)-adrenoceptors and dopamine D1 receptors.
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PMID:Phosphorylation of protein phosphatase-1 inhibitors, inhibitor-1 and DARPP-32, in renal medulla. 1108 May 16

The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-alpha activity affects dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure.
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PMID:PKC-alpha regulates cardiac contractility and propensity toward heart failure. 1499 Oct 46

Sorcin is a 21.6-kDa Ca(2+) binding protein of the penta-EF hand family. Several studies have shown that sorcin modulates multiple proteins involved in excitation-contraction (E-C) coupling in the heart, such as the cardiac ryanodine receptor (RyR2), L-type Ca(2+) channel, and Na(+)-Ca(2+) exchanger, while it has also been shown to be phosphorylated by cAMP-dependent protein kinase (PKA). To elucidate the effects of sorcin and its PKA-dependent regulation on E-C coupling in the heart, we identified the PKA-phosphorylation site of sorcin, and found that serine178 was preferentially phosphorylated by PKA and dephosphorylated by protein phosphatase-1. Isoproterenol allowed sorcin to translocate to the sarcoplasmic reticulum (SR). In addition, adenovirus-mediated overexpression of sorcin in adult rat cardiomyocytes significantly increased both the rate of decay of the Ca(2+) transient and the SR Ca(2+) load. An assay of oxalate-facilitated Ca(2+) uptake showed that recombinant sorcin increased Ca(2+) uptake in a dose-dependent manner. These data suggest that sorcin activates the Ca(2+)-uptake function in the SR. In UM-X7. 1 cardiomyopathic hamster hearts, the relative amount of sorcin was significantly increased in the SR fraction, whereas it was significantly decreased in whole-heart homogenates. In failing hearts, PKA-phosphorylated sorcin was markedly increased, as assessed using a back-phosphorylation assay with immunoprecipitated sorcin. Our results suggest that sorcin activates Ca(2+)-ATPase-mediated Ca(2+) uptake and restores SR Ca(2+) content, and may play critical roles in compensatory mechanisms in both Ca(2+) homeostasis and cardiac dysfunction in failing hearts.
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PMID:Sorcin interacts with sarcoplasmic reticulum Ca(2+)-ATPase and modulates excitation-contraction coupling in the heart. 1575 88

Our knowledge and understanding of the normal and diseased heart has advanced significantly over the past decade. Evidence indicates that several signaling pathways involved in the induction of cardiac disease and heart failure are associated with abnormal calcium handling by the sarcoplasmic reticulum proteins: calcium-ATPase pump and phospholamban. Indeed, the failing heart is characterized by impaired removal of cytosolic calcium, reduced loading of the cardiac sarcoplasmic reticulum, and defective calcium release, culminating in impairment of cardiac diastolic and systolic function. This review summarizes studies which highlight the key role of the sarcoplasmic reticulum proteins, calcium-ATPase pump and phospholamban, in the regulation of cardiac function; the significance of the phospholamban interaction with the calcium-ATPase pump through transgenic animal models; the recent findings of the inhbitor-1 of protein phosphatase-1 as a new potential therapeutic agent in heart failure; and finally, the discoveries of human phospholamban mutations leading to disease states.
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PMID:Phospholamban: a key determinant of cardiac function and dysfunction. 1643 4


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