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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 130 kDa atrial natriuretic factor receptor (ANF-R1) purified from bovine adrenal zona glomerulosa is phosphorylated in vitro by serine/threonine protein kinases such as cAMP-, cGMP-dependent and protein kinase C. This phosphorylation is independent of the presence of ANF (99-126) and there is no detectable intrinsic kinase activity associated with the ANF-R1 receptor or with its activated form. In bovine adrenal zona glomerulosa cells, TPA (phorbol ester) induces a marked inhibition of the ANF-stimulated cGMP accumulation as well as of the membrane ANF-sensitive guanylate cyclase catalytic activity without any change in the binding capacity or affinity for 125I-ANF. However, we have demonstrated a significant 32P incorporation in the ANF-R1 receptor of the TPA-treated cells. The effect of TPA on the zona glomerulosa ANF-R1 receptors was abolished by calphostin C, a specific protein kinase C inhibitor. Altered ANF actions due to blunted response of guanylate cyclase to ANF could be a consequence of the ANF receptor phosphorylation by excessive activity of protein kinase C and might be involved in the pathogenesis of hypertension.
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PMID:Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation. 128 Mar 21

The signalling mechanism and cellular targets of the AT2 receptor are still unknown. We report that angiotensin II (Ang II) inhibits basal and atrial natriuretic peptide stimulated particulate guanylate cyclase (pGC) activity through AT2 receptors in rat adrenal glomerulosa and PC12W cells. This inhibition is blocked by the phosphotyrosine phosphatase (PTPase) inhibitor orthovanadate but not by the Ser/Thr phosphatase inhibitor okadaic acid, suggesting the involvement of a PTPase in this process. Moreover, Ang II induces a rapid, transient and orthovanadate sensitive dephosphorylation of phosphotyrosine containing proteins in PC12W cells. Our findings suggest that AT2 receptors signal through stimulation of a PTPase and that this mechanism is implicated in the regulation of pGC activity. This observation is also the first example of hormonal inhibition of basal pGC activity.
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PMID:The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. 134 47

Phenotype, growth, and functional characteristics of glomerular mesangial "myofibroblasts" are under the control of multiple hormones, vasoactive agents, autacoids, and cytokines. Several parallel signal transduction pathways couple receptor occupancy with functional changes, including phospholipases C, A2, and D breakdown of membrane phospholipids, and adenylate/guanylate cyclase activation. Changes of cytosolic ion concentrations, cyclic nucleotide accumulation, and eicosanoid biosynthesis are currently interpreted as intracellular signals for protein kinase activation. Phosphorylation of multiple substrates by serine/threonine kinases C, A, and G or by tyrosine kinases directly coupled to receptors, is a final step in cell activation. Cross-talk between signal transduction pathways, along with the release of eicosanoids and cytokines acting as intercellular mediators, provides the potential for interactive regulation of glomerular cell functions.
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PMID:Signal transduction in mesangial cells. 135 Sep 29

Tetrahymena calmodulin (CaM) differs from mammalian CaM in its ability to activate Tetrahymena guanylate cyclase. Of 12 differences in amino acid sequence, two occur near the carboxyl terminus (Gln-143----Arg and Thr-146----deletion). To investigate the functional significance of the carboxyl-terminal region in activation of the guanylate cyclase, three mutated CaMs were engineered by using cassette mutagenesis of rat CaM cDNA: Gln-143----Arg (CaM.A), Thr-146----deletion (CaM.D), and Gln-143----Arg/Thr-146 deletion (CaM.AD). Recombinant wild type CaM (wCaM), CaM.A, CaM.D, and CaM.AD were indistinguishable in their ability to activate cyclic AMP phosphodiesterase. The two mutated CaMs (CaM.A and CaM.AD) with the Gln-143 replacement activated guanylate cyclase of Tetrahymena plasma membrane in the presence of Ca2+, with the maximal activation being half of that produced by Tetrahymena CaM. In contrast, neither CaM.D nor wCaM could stimulate the cyclase activity. A CaM antagonist, W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide), prevented the cyclase activation by either Tetrahymena CaM, CaM.A, or CaM.AD. Thus, we conclude that Arg-143 is in a region of the molecule involved in activation of Tetrahymena guanylate cyclase. The data also suggest that the cyclase activation by Tetrahymena CaM requires complex macromolecular interactions between the entire CaM molecule and the enzyme.
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PMID:Site-directed mutagenesis of glutamine residue of calmodulin. Activation of guanylate cyclase of Tetrahymena plasma membrane. 196 9

Two peptides, speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly) and resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-Leu-NH2), which activate sperm respiration and motility and elevate cyclic GMP concentrations in a species-specific manner, were tested for effects on guanylate cyclase activity. The guanylate cyclase of sea urchin spermatozoa is a glycoprotein and it is localized entirely on the plasma membrane. When intact sea urchin sperm cells were incubated with the appropriate peptide for time periods as short as 5 s and subsequently homogenized in detergent, guanylate cyclase activity was found to be as low as 10% of the activity of cells not treated with peptide. The peptides showed complete species specificity and analogues of one peptide (speract) caused decreases in enzyme activity coincident with their receptor binding properties. The peptides did not inhibit enzyme activity when added after detergent solubilization of the enzyme. When detergent-solubilized spermatozoa were incubated at 22 degrees C, guanylate cyclase activity declined in previously nontreated cells to the peptide-treated level. The rate of decline was dependent on temperature and protein concentration. When spermatozoa were first incubated with 32P, the decrease in guanylate cyclase activity was accompanied by a shift in the apparent molecular weight of a major plasma membrane protein (160,000-150,000) and a loss of 32P label from the 160,000 band. Other agents (Monensin A, NH4Cl) which were capable of stimulating sperm respiration and motility also caused decreases of guanylate cyclase activity when added to intact but not detergent-solubilized spermatozoa. The maximal decrease in guanylate cyclase activity occurred 5-10 min after addition of these agents. The enzyme response to Monensin A required extracellular Na+ suggestive that the ionophore caused the effect on guanylate cyclase activity by virtue of its ability to catalyze Na+/H+ exchange. These studies demonstrate that guanylate cyclase activity of sperm cells can be altered by the specific interaction of egg-associated peptides with their plasma membrane receptors.
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PMID:Receptor-mediated regulation of guanylate cyclase activity in spermatozoa. 286 Dec 1

The sea urchin egg peptides speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly) and resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Arg-Leu-NH2) bind to spermatozoa of the homologous species (Lytechinus pictus or Arbacia punctulata, respectively) and cause transient elevations of cyclic GMP concentrations (Hansbrough, J. R., and Garbers, D. L. (1981) J. Biol. Chem. 256, 1447-1452). The addition of these peptides to spermatozoan membrane preparations caused a rapid and dramatic (up to 25-fold) activation of guanylate cyclase. The peptide-induced activation of guanylate cyclase was transient, and the subsequent decline in enzyme activity coincided with conversion of a high Mr (phosphorylated) form of guanylate cyclase to a low Mr (dephosphorylated) form. When membranes were incubated at pH 8.0, the high Mr form was converted to the low Mr form without substantial changes in basal enzyme activity. However, the peptide-stimulated activity of the low Mr form of guanylate cyclase was much less than the peptide-stimulated activity of the high Mr form. Activation of the low Mr form by peptide was not transient and persisted for at least 10 min. In addition, the pH 8.0 treatment that caused the Mr conversion of guanylate cyclase also caused an increase in the peptide-binding capacity of the membranes. We propose a model in which activation of the membrane form of guanylate cyclase is receptor-mediated; the extent of enzyme activation is modulated by its phosphorylation state.
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PMID:Receptor-mediated activation of spermatozoan guanylate cyclase. 287 90

GGGYG-resact (Gly-Gly-Gly-Tyr-Gly-Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg -Leu-NH2) was synthesized and shown to possess the same respiration-stimulating activity and receptor-binding ability as resact. The incubation of intact sperm cells with radioiodinated peptide, 125I-GGGYG-resact, and the chemical cross-linking reagent, disuccinimidyl suberate, resulted in the appearance of a single, major radioactive band of apparent molecular weight 160,000 (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). The interaction was specific since 150 nM nonradioactive resact but not speract (200 nM) blocked formation of the radioactive band. The radioactive, cross-linked protein co-migrated with 32P-labeled guanylate cyclase and could be immunoprecipitated with a polyclonal antibody raised in rabbits against the sperm guanylate cyclase. The incubation of intact cells with NH4Cl resulted in the partial dephosphorylation of guanylate cyclase and a change in its apparent molecular weight from 160,000 to 150,000; NH4Cl also caused the same conversion in the apparent molecular weight of the cross-linked protein. These data demonstrate that an analogue of resact can be covalently coupled to guanylate cyclase with the specificity predicted for the peptide receptor.
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PMID:Covalent coupling of a resact analogue to guanylate cyclase. 287 82

Speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly), a peptide obtained from the culture medium of Strongylocentrotus purpuratus eggs, stimulates the respiration and motility of S. purpuratus spermatozoa under appropriate conditions. Resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-LeuNH2), a peptide obtained from Arbacia punctulata eggs also stimulates the metabolism and motility of A. punctulata spermatozoa, however, it fails to stimulate S. purpuratus spermatozoa. Early biochemical responses of the spermatozoa to the egg peptides include a net H+ efflux and elevations of cyclic AMP and cyclic GMP concentrations. In addition, in A. punctulata spermatozoa, a major plasma membrane protein is modified in response to resact such that its apparent molecular weight shifts from 160,000 to 150,000. If cells are incubated with 32P, the 160,000 molecular weight form of the protein becomes radiolabeled; subsequent addition of resact causes a rapid loss of 32P from the protein. The plasma membrane protein appears to be the enzyme, guanylate cyclase; coincident with the shift in apparent molecular weight, enzyme activity decreases by as much as 90%. Since speract fails to cause these responses in A. punctulata, it can be concluded that the events are receptor-mediated.
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PMID:Peptides associated with eggs: mechanisms of interaction with spermatozoa. 288 30

Dictyostelium discoideum cells contain a single ras gene (Dd-ras) that is highly homologous to mammalian ras genes. Cell transformation with a vector carrying a ras gene with a (glycine----threonine) missense mutation at position 12 causes an altered morphogenesis. Extracellular cAMP signals regulate morphogenesis and induce chemotaxis and the activation and subsequent desensitization of adenylate and guanylate cyclase. cAMP signal transduction was investigated in Dd-ras-transformed cells. Transformants that overexpress the mutated Dd-ras-Thr12 gene show normal activation and desensitization of adenylate cyclase and normal activation of guanylate cyclase. However, cAMP induces a stronger desensitization of guanylate cyclase stimulation in the Dd-ras-Thr12 transformant than in transformants overexpressing the Dd-ras-Gly12 wild-type gene or in untransformed cells. This effect was correlated with a reduced chemotactic sensitivity of the transformant expressing the mutated Dd-ras-Thr12 gene.
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PMID:Aberrant transmembrane signal transduction in Dictyostelium cells expressing a mutated ras gene. 288 43

These studies are the first to report egg peptide-mediated stimulation of protein phosphorylation in spermatozoa. Speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly) or resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-Leu-NH2) stimulated the incorporation of 32P into various proteins of isolated spermatozoan membranes in the presence, but not absence, of GTP. The Mr of three of the phosphorylated proteins were 52,000, 75,000, and 100,000. GTP gamma S (guanosine 5'-O-(3-thiotriphosphate] but not GDP beta S (guanosine 5'-O-(2-thiodiphosphate] or GMP-PNP (guanylyl imidodiphosphate) also supported the peptide-mediated stimulation of protein phosphorylation. The peptides markedly stimulated guanylate cyclase activity, and GTP gamma S or GTP but not GMP-PNP served as effective substrates for the enzyme. The accumulation of cyclic AMP was not stimulated by the peptides. Subsequently, it was shown that added cyclic GMP or cyclic AMP increased 32P incorporation into the same membrane proteins as those observed in the presence of peptide and GTP. The amount of cyclic GMP (up to 3 microM) formed by membranes in the presence of peptide and 100 microM GTP equated with the amount of added cyclic GMP required to increase the 32P content of a Mr 75,000 protein selected for further study. 32P-Peptide maps of the Mr 75,000 protein indicated that the same domains were phosphorylated in response to cyclic nucleotides or to egg peptide and GTP. Intact cells were subsequently incubated with 32P to determine if the radiolabeled proteins observed in isolated membranes also would be obtained in intact cells. The 32P contents of proteins of Mr 52,000, 75,000, and 100,000 were significantly increased by the addition of resact. Peptide maps confirmed that the increased 32P incorporation obtained in a Mr 75,000 protein of isolated membranes occurred on the same protein domains as the 32P found on the Mr 75,000 protein of intact cells. These results suggest that a GTP or GTP gamma S requirement for peptide-mediated protein phosphorylation in spermatozoan membranes is mainly due to the enhanced formation of cyclic GMP, and it therefore is likely that peptide-induced elevations of cyclic nucleotide concentrations in spermatozoa are responsible for the specific increases in 32P associated with at least three sperm proteins, all apparently localized on the plasma membrane.
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PMID:Receptor-mediated phosphorylation of spermatozoan proteins. 289 Jun 31


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