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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we examined the effects of guanine nucleotides on vasopressin-induced osmotic water flow and sodium transport in the 14-h preincubated frog bladder. We also examined the effects of the adenylate cyclase-cyclic AMP and cyclic AMP-dependent protein kinase system in the bladder's epithelial cells. Gpp(NH)p significantly enhanced vasopressin-induced water flow while it did not affect cyclic AMP-induced water flow. However, Gpp(NH)p did not enhance the vasopressin-induced increment of sodium transport across the frog bladder. The adenylate cyclase activity of the crude homogenate was enhanced by vasopressin, Gpp(NH)p and NaF. The effects of Gpp(NH)p and vasopressin, at their maximum doses, on the enzyme activities were additive, while other combinations were not. Specific Gpp(NH)p binding sites were found in the pellet fraction after 2,400 X g centrifugation. No direct effect on the protein kinase activity was observed in the presence of 10(-6) M nucleotides, such as GTP, GDP, GMP, CTP, UTP, ITP and Gpp(NH)p. Cyclic AMP stimulated the phosphorylation of discrete protein bands, however, Gpp(NH)p did not influence cyclic AMP-dependent protein phosphorylation of crude homogenate of the bladder's epithelial cells. These results suggest the guanine nucleotides stimulate the vasopressin-induced osmotic water flow in frog bladder by enhancing the vasopressin-mediated adenylate cyclase activity, so that accumulated cyclic AMP might activate cyclic AMP-dependent protein kinase.
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PMID:Effects of guanine nucleotides on vasopressin-induced water flow and sodium transport of the frog bladder. 660 7

Methyl lidocaine is an experimental anti-arrhythmic drug which has been shown to enhance the biosynthesis of phosphatidyl-inositol (PI) in the hamster heart. In this study, the effect of methyl lidocaine on enzymes involved in the biosynthesis of PI in the heart was examined. When the hamster heart was perfused with labelled methyl lidocaine, the majority of the compound was not metabolized after perfusion. The direct action of methyl lidocaine on an enzyme was studied by the presence of the drug in enzyme assays, whereas its indirect action was studied by assaying the enzyme activity in the heart after methyl lidocaine perfusion. CTP:phosphatidic acid cytidylyl-transferase, a rate-limiting enzyme in PI biosynthesis, was stimulated by methyl lidocaine in a direct manner. Kinetic studies revealed that methyl lidocaine caused a change in the affinity between the enzyme and phosphatidic acid and resulted in the enhancement of the reaction. Alternatively, acyl-CoA:lysophosphatidic acid acyltransferase, another key enzyme for PI biosynthesis, was not activated by the presence of methyl lidocaine. However, the enzyme activity was stimulated in hearts perfused with methyl lidocaine. The enhancement of the acyl-transferase by methyl lidocaine perfusion was found to be mediated via the adenylate cyclase cascade with the elevation of the cyclic AMP level. The stimulation of protein kinase A activity by cyclic AMP resulted in the phosphorylation and activation of the acyltransferase. Interestingly, the activity of protein kinase C was not stimulated by methyl lidocaine perfusion. We conclude that the enhancement of PI biosynthesis by methyl lidocaine in the hamster heart resulted from the direct activation of the cytidylyltransferase, as well as the phosphorylation and subsequent activation of the acyltransferase.
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PMID:The modulation of phosphatidylinositol biosynthesis in hamster hearts by methyl lidocaine. 763 4

The role of the C-terminal domain of CTP: phosphocholine cytidylyltransferase (CT) was explored by the creation of a series of deletion mutations in rat liver cDNA, which were expressed in COS cells as a major protein component. Deletion of up to 55 amino acids from the C-terminus had no effect on the activity of the enzyme, its stimulation by lipid vesicles or on its intracellular distribution between soluble and membrane-bound forms. However, deletion of the C-terminal 139 amino acids resulted in a 90% decrease in activity, loss of response to lipid vesicles and a significant decrease in the fraction of membrane-bound enzyme. Identification of the domain that is phosphorylated in vivo was determined by analysis of 32P-labelled CT mutants and by chymotrypsin proteolysis of purified CT that was 32P-labelled in vivo. Phosphorylation was restricted to the C-terminal 52 amino acids (domain P) and occurred on multiple sites. CT phosphorylation in vitro was catalysed by casein kinase II, cell division control 2 kinase (cdc2 kinase), protein kinases C alpha and beta II, and glycogen synthase kinase-3 (GSK-3), but not by mitogen-activated kinase (MAP kinase). Casein kinase II phosphorylation was directed exclusively to Ser-362. The sites phosphorylated by cdc2 kinase and GSK-3 were restricted to several serines within three proline-rich motifs of domain P. Sites phosphorylated in vitro by protein kinase C, on the other hand, were distributed over the N-terminal catalytic as well as the C-terminal regulatory domain. The stoichiometry of phosphorylation catalysed by any of these kinases was less than 0.2 mol P/mol CT, and no effects on enzyme activity were detected. This study supports a tripartite structure for CT with an N-terminal catalytic domain and a C-terminal regulatory domain comprised of a membrane-binding domain (domain M) and a phosphorylation domain (domain P). It also identifies three kinases as potential regulators in vivo of CT, casein kinase II, cyclin-dependent kinase and GSK-3.
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PMID:Functions of the C-terminal domain of CTP: phosphocholine cytidylyltransferase. Effects of C-terminal deletions on enzyme activity, intracellular localization and phosphorylation potential. 765 14

This report demonstrates that platelets possess P2 purinoceptors with unique properties that distinguish them from the ADP (P2T) receptor. Extracellular ATP, and its poorly hydrolyzable analogues, inhibit collagen- and U46619 (a thromboxane mimetic)-induced platelet aggregations. Adenosine deaminase was without effect on ATP action while reversing the inhibitory effect of adenosine. A unique aspect of the P2 receptor is the sensitivity to UTP and CTP and insensitivity to GTP. The rank order of inhibition by beta gamma-methylene ATP, alpha beta-methylene ATP > ATP indicates that a P2x-like receptor is present on the platelet membrane. This conclusion is further supported by the nearly complete desensitization to ATP by pre-exposure of platelets to alpha beta-methylene-ATP. However, unlike previously described P2x purinoceptors, the inhibition of platelet aggregation by extracellular ATP appears to result, at least in part, from the ATP-induced increase of intracellular cyclic AMP levels apparently coupled through a Gs protein. The combined addition of iloprost (0.14 to 1.39 nM) and ATP (18 microM) or ATP (20-40 microM) and the phosphodiesterase inhibitor theophylline (0.5 to 1 mM) synergistically inhibited platelet aggregation implying a common interactive site with adenylate cyclase. This is further substantiated by the ability of the adenylate cyclase inhibitor, 2',5'-dideoxyadenosine, to abrogate the inhibitory effects of ATP. The protein kinase A (PKA) inhibitor H1004 blocks ATP inhibition of platelet aggregation while the protein kinase C inhibitor H7 did not. This implies that the generation of cyclic AMP, with the subsequent activation of PKA and phosphorylation of selected proteins is required, in part, for the action of ATP.
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PMID:Occupancy of P2 purinoceptors with unique properties modulates the function of human platelets. 768 12

We have examined phosphorylation of the rat liver glucocorticoid receptor (GR) and GR-associated protein kinase (PK) activity in the immunopurified receptor preparations. Affinity labeling of hepatic cytosol with [3H]dexamethasone 21-mesylate showed a covalent association of the steroid with a 94 kDa protein. GR was immunopurified with antireceptor monoclonal antibody BuGR2 (Gametchu & Harrison, Endocrinology 114: 274-279, 1984) to near homogeneity. A 23 degrees C incubation of the immunoprecipitated protein A-Sepharose adsorbed GR with [gamma-32P]ATP,Mg2+ and the catalytic subunit of cAMP-dependent PK (cAMP-PK) from bovine heart, led to an incorporation of radioactivity in the 94 kDa protein. Phosphorylation of GR was not evident in the absence of the added kinase. Of the radioinert nucleotides (ATP, GTP, UTP or CTP) tested, only ATP successfully competed with [gamma-32P]ATP demonstrating a nucleotide specific requirement for the phosphorylation of GR. Other divalent cations, such as Mn2+ or Ca2+, could not be substituted for Mg2+ during the phosphorylation reaction. Phosphorylation of GR was sensitive to the presence of the protein kinase inhibitor, H-8, an isoquinoline sulfonamide derivative. In addition, the incorporation of radioactivity into GR was both time- and temperature-dependent. The phosphorylation of GR by cAMP-PK was independent of the presence of hsp-90 and transformation state of the receptor. The results of this study demonstrate that GR is an effective substrate for action of cAMP-PK and that the immunopurified protein A-Sepharose adsorbed GR lacks intrinsic kinase activity but can be conveniently used for the characterization of the phosphorylation reaction in the presence of an exogenous kinase.
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PMID:Phosphorylation of immunopurified rat liver glucocorticoid receptor by the catalytic subunit of cAMP-dependent protein kinase. 796 99

A previous study showing that ethanol (ETOH) blocked [3H]choline incorporation into phosphatidylcholine (PC) suggested an inhibition of PC biosynthesis in human leukemic monocyte-like U937 cells. The mechanism of the inhibitory action of ETOH was investigated. Cells were pulsed with [3H]choline for 30 min and chased in the presence or absence of ETOH for up to 6 h. PC biosynthesis was inhibited drastically within 1 h after exposure to ETOH which increased intracellular cAMP appreciably. After a 3-h treatment, ETOH significantly inhibited both choline kinase (CK) and the cytosolic CTP: cholinephosphate cytidylyltransferase (CT). The inactivated CT was no longer stimulated by exogenous phosphatidylglycerol (PG). There was no evidence for redistribution of CT activity between cytosol and microsomes. When cells were exposed to 8-Bromo-cAMP ranging from 100 to 300 microM, PC biosynthesis remained unaffected despite the drastically elevated cAMP. These results seem to suggest that the raised cAMP is not a prerequisite for the inhibition of PC biosynthesis in U937 cells. Following pretreatment with protein kinase inhibitors (H-89 and K-252a), PC biosynthesis was decreased significantly and the inhibitory effect of ETOH was potentiated. Taken together, our results suggest that the inhibition of PC biosynthesis and the inhibitory effect of ETOH are independent of the activation of cAMP-dependent protein kinase. Unlike protein kinase inhibitors, pretreatment with tyrosine kinase inhibitors (erbstatin, genistein and tyrphostin 25) resulted in differential effects on PC biosynthesis and on the inhibitory action of ETOH. Genistein stimulated PC biosynthesis by 30 per cent as well as partially preventing/reversing the ETOH action, while tyrphostin 25 produced a synergistic inhibition. The relevance of tyrosine phosphorylation/dephosphorylation to the regulation of PC biosynthesis and ETOH action remains to be established.
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PMID:Mechanism by which ethanol inhibits phosphatidylcholine biosynthesis in human leukemic monocyte-like U937 cells. 816 30

1. The differential effects of inhibitors of protein kinase (PK) or tyrosine kinase (TK) on phosphatidylcholine (PC) biosynthesis in monocyte-like U937 cells were compared in pulse-chase-studies in which the cells prelabelled with [3H]choline for 30 min were chased in the absence or presence of kinase inhibitors. 2. PKA inhibitor (H-89) decreased the label incorporation into PC, while PKA activator (8-BrcAMP) had no effect. 3. PKC inhibitors (chelerythrine and hypericin) inhibited PC biosynthesis; on the other hand, PKC activator (SC-10) was stimulatory. 4. The inhibition of PC biosynthesis by H-89 and chelerythrine was accompanied by the inactivation of CTP: cholinephosphate cytidylyltransferase (CT). 5. In contrast, TK inhibitor (genistein) markedly stimulated CT and PC biosynthesis, while erbstatin and tyrphostin No. 25 showed no effect.
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PMID:Differential regulations of phosphatidylcholine biosynthesis in U937 cells by inhibitors of protein and tyrosine kinases. 817 53

The synthesis of phosphatidylinositol (PI) 4-phosphate and PI 4,5-bisphosphate in the yeast Saccharomyces cerevisiae is stimulated by glucose. PI 4-kinase (ATP:phosphatidylinositol 4-phosphotransferase, EC 2.7.1.67) catalyzes the committed step in the synthesis of these phosphoinositides. Previous studies have suggested that the glucose effect on phosphoinositide synthesis is mediated by cellular levels of ATP and ADP and by the RAS/cAMP pathway. Using purified preparations of the membrane-associated 45- and 55-kDa forms of PI 4-kinase, we examined the regulation of these activities by nucleotides and cAMP-dependent protein kinase. MgADP was a potent inhibitor of both forms of the enzyme. Detailed kinetic analyses of the 45- and 55-kDa enzymes using Triton X-100/PI-mixed micelles showed that MgADP was a competitive inhibitor (Ki = 0.14 and 0.25 mM, respectively) with respect to MgATP and a noncompetitive inhibitor (Ki = 1.3 and 0.9 mM, respectively) with respect to PI. The Ki values for MgADP were about 2-fold lower than the Km values the enzymes have for their substrate MgATP and about 2-fold lower than the cellular concentration of ADP. The 45- and 55-kDa forms of PI 4-kinase activity were regulated differentially by CTP, an important nucleotide involved in phospholipid biosynthesis. Whereas the 55-kDa PI 4-kinase was inhibited by CTP, the 45-kDa enzyme was unaffected by CTP. CTP was a mixed type of inhibitor (Ki = 1.5 mM) with respect to MgATP and a noncompetitive inhibitor (Ki = 4 mM) with respect to PI. The Ki value for CTP was 4-fold higher than the Km value for MgATP and 7-fold higher than the cellular concentration of CTP. The 45- and 55-kDa PI 4-kinases were neither phosphorylated nor regulated by cAMP-dependent protein kinase. These results did not support the previous conclusion that PI 4-phosphate synthesis was mediated by the RAS/cAMP pathway. Our kinetic studies supported the conclusion that the glucose effect on the synthesis of PI 4-phosphate was mediated by cellular levels of ATP and ADP through the regulation of membrane-associated PI 4-kinase activity.
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PMID:Regulation of the 45- and 55-kDa forms of phosphatidylinositol 4-kinase from the yeast Saccharomyces cerevisiae by nucleotides. 838 5

1. Single channel current recordings were used to study the characteristics of a large conductance Ca(2+)-activated K+ (BKCa) channel present in neurones acutely dissociated from the rat motor cortex. Application of ATP to the intracellular surface of excised inside-out patches produced a large, concentration-dependent increase in BKCa channel activity. 2. This ATP-mediated activation was dependent upon the presence of Mg2+ in the intracellular bathing solution and was diminished by the phosphatases 2,3-butanedione monoxime (BDM) or alkaline phosphatase and by the protein kinase inhibitors staurosporine, H-7 and PKI. 3. ADP stimulated BKCa channel activity in a Mg(2+)-dependent manner, an action also inhibited by the concomitant application of PKI or BDM. The effect of ADP was reduced by application of hexokinase and glucose or by application of the adenylate kinase inhibitor Ap5A. 4. Of other nucleotides tested, only CTP consistently activated BKCa channel activity. 5. Using the cell-attached configuration, bath application of forskolin or dibutyryl cAMP stimulated BKCa channel activity. 6. It is concluded that BKCa channel activity in the rat motor cortex is subject to modulation by the activity of a closely associated kinase. The ability of cAMP activators to stimulate BKCa channel activity in the intact cell suggests that this system may be of physiological importance.
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PMID:Characterization of an ATP-modulated large conductance Ca(2+)-activated K+ channel present in rat cortical neurones. 856 73

In LTK- cells stably transfected with rat D1A receptor cDNA, fenoldopam, a D1 agonist, increased phosphatidylinositol 4, 5-bisphosphate hydrolysis in a time-dependent manner. In the cytosol, phospholipase C (PLC) activity increased (50 +/- 7%) in 30 s, returned to basal level at 4 h, and decreased below basal values by 24 h; in the membrane, PLC activity also increased (36 +/- 13%) in 30 s, returned to basal level at 10 min, and decreased below basal value at 4 and 24 h. Fenoldopam also increased PLC-gamma protein in a time-dependent manner. The latter was blocked by the D1 antagonist SKF83742 and by a D1A antisense oligodeoxynucleotide, indicating involvement of the D1A receptor. The fenoldopam-induced increase in PLC-gamma and activity was mediated by protein kinase A (PKA) since it was blocked by the PKA antagonist Rp-8-CTP-adenosine cyclic 3':5'-monophosphorothioate (Rp-8-CTP-cAMP-S) and mimicked by direct stimulation of adenylyl cyclase with forskolin or by a PKA agonist, Sp-cAMP-S. Protein kinase C (PKC) was also involved, since the fenoldopam-induced increase in PLC-gamma protein was blocked by two different PKC inhibitors, calphostin C and chelerythrine; calphostin C also blocked the fenoldopam-induced increase in PLC activity. In addition, forskolin and a PKA agonist, Sp-8-CTP-cAMP-S, increased PKC activity, and direct stimulation of PKC with phorbol 12-myristate 13-acetate increased PLC-gamma protein and activity, effects that were blocked by calphostin C. We suggest that the D1A-mediated stimulation of PLC occurs as a result of PKA activation. PKA then stimulates PLC-gamma in cytosol and membrane via activation of PKC.
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PMID:Dopamine D1A receptor regulation of phospholipase C isoform. 870 41


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