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 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

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

Speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly), a peptide obtained from eggs, has been shown to bind to a plasma membrane receptor of Lytechinus pictus spermatozoa. Here, we show that the addition of speract to intact cells caused the appearance of a new protein-staining band (Mr = 140,000) on sodium dodecyl sulfate (SDS) polyacrylamide gels; concomitantly, a protein of apparent molecular weight (Mr) 150,000 disappeared. Guanylate cyclase activity also decreased approximately 50% after the addition of speract to intact cells. Plasma membranes were subsequently prepared from spermatozoa in the presence of fluoride at pH 6.0, conditions that resulted in retention of the speract receptor and the Mr 150,000 protein. Addition of speract to the membranes resulted in a disappearance of the Mr 150,000 protein and the appearance of a Mr 140,000 protein. Coincident with the apparent change in molecular weight, guanylate cyclase activity decreased 30% at maximal speract concentrations. A physiological event that occurs in the intact cell in response to speract can now be reproduced in isolated plasma membranes; it should, therefore, now be possible to define the molecular events that occur as a result of speract: receptor interaction.
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PMID:Receptor-mediated responses of plasma membranes isolated from Lytechinus pictus spermatozoa. 288 84

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

Here for the first time we report the successful detergent-solubilization of the speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly) receptor and the subsequent activation of guanylate cyclase in response to receptor occupation. Sea urchin sperm membranes treated with a solution containing 0.5% LubrolR PX and 0.5% EmulphogeneR in the presence of MgCl2 and NaF released both the speract receptor and guanylate cyclase activity into solution. The solubilized apparent receptor was not sedimented at 400,000 x g x 15 min and was not retained by glass microfiber filters. In the presence of 125I-GGG(Y2)speract and dissuccinimidyl suberate, a major radioactive band at about Mr = 77,000 and minor bands at Mr = 35,000 and 150,000 were cross-linked. Speract but not resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-LeuNH2) competed in the cross-linking reaction. The amount of 125I-GGG(Y2)speract bound to solubilized receptor did not increase in a linear manner as a function of added protein but instead was concave upward. The addition of speract but not resact to the solubilized preparation resulted in the activation of the enzyme guanylate cyclase; the extent of stimulation was dependent on the amount of enzyme protein added and also was concave upward. Approximately 900 nM speract half-maximally activated guanylate cyclase. These data suggest that the speract receptor and guanylate cyclase are closely apposed, even in detergent, or that they are the same molecule.
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PMID:Receptor-mediated activation of detergent-solubilized guanylate cyclase. 290 84

Extracts of mammalian atria, but not ventricles, induce marked diuresis, natriuresis, and reduction in blood pressure when infused systemically in rats and dogs. These extracts also inhibit aldosterone biosynthesis and renal renin release. Natriuretic peptides, 21 amino acids and longer, have been isolated from atria of rodents and man, and share a nearly homologous amino acid sequence at the carboxyterminus. Natriuretic activity resides in a 17-amino acid ring formed by a disulfide bridge, and the C-terminal Phe-Arg appears necessary for full biological potency. The deoxyribonucleic acid-encoding atrial natriuretic peptides have been cloned and the gene structure elucidated. Reduction of the diuretic and natriuretic responses to an acute volume load by right atrial appendectomy first suggested a role for atrial peptides in the physiological response to plasma volume expansion. Subsequently, release of peptides with natriuretic and spasmolytic properties from isolated heart preparations in response to right atrial distension was demonstrated by bioassay and radioimmunoassay. The presence of these peptides in normal rat and human plasma in concentrations of 20-100 pM, and the findings of increased levels in response to acute and chronic plasma volume expansion, rapid atrial tachyarrhythmias, systemic hypertension, congestive heart failure, and renal insufficiency imply that they play an important role in body fluid homeostasis. The mechanisms by which atrial peptides increase renal salt and water excretion are as yet unclear. Renal vascular effects have been consistently demonstrated, and limited evidence for direct actions on tubule ion transport has also been reported recently. In vitro, these peptides cause precontracted vascular and nonvascular smooth muscle to relax, mediated by a direct action on smooth muscle cells. Specific receptors for these peptides have been characterized in crude membranes prepared from whole kidney homogenates and adrenal glomerulosa cells, in intact glomeruli and cultured glomerular mesangial cells, and in intact bovine aortic smooth muscle and endothelial cells. Natriuretic peptides stimulate cyclic guanosine monophosphate accumulation in target tissues, and augment particulate guanylate cyclase activity in membrane fractions, suggesting that cyclic guanosine monophosphate is the second messenger mediating their cellular action.
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PMID:George E. Brown memorial lecture. Role of atrial peptides in body fluid homeostasis. 301 7

A peptide (resact) associated with the eggs of the sea urchin, Arbacia punctulata, which stimulates sperm respiration rates by 5-10-fold, was purified and its amino acid sequence was determined. The sequence was found to be Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-Leu-NH2. The peptide was subsequently synthesized by solid phase methods, amidated at the carboxyl-terminal Leu, and shown to be identical to the isolated, native material. The peptide half-maximally stimulated A. punctulata spermatozoan respiration at 0.5 nM and half-maximally elevated cyclic GMP concentrations at 25 nM at an extracellular pH of 6.6. The increase in oxygen consumption was coupled with a stimulation of motility. However, at elevated extracellular pH (pH 8.0), resact failed to appreciably stimulate respiration while the elevations of cyclic GMP continued to occur. Resact did not cross-react with sperm cells obtained from Lytechinus pictus or Strongylocentrotus purpuratus; a peptide (speract) obtained from S. purpuratus eggs (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly) which activates S. purpuratus sperm respiration did not stimulate A. punctulata spermatozoa. Resact caused a shift in the apparent molecular weight (160,000-150,000) of a major sperm plasma membrane protein; as with cyclic GMP elevations, this response was evident at extracellular pH values of both 6.6 and 8.0. The protein exists in the cell as a phosphoprotein and 32P is released coincident with the molecular weight change. Approximately 115 nM resact caused one-half-maximal conversion of the 160,000-dalton protein after 1 min of incubation. Resact caused the apparent molecular weight conversion of the protein within 5 s and appeared to do so in an irreversible manner. The molecular weight change of the protein was also observed after the addition of monensin A (25 microM) and NH4Cl (40 mM), two agents known to elevate intracellular pH and to increase sperm respiration rates. The membrane protein appears to be the enzyme guanylate cyclase, but since concentrations of resact causing one-half-maximal conversion of the Mr = 160,000 form of the enzyme are about 250 times higher than those causing one-half-maximal stimulation of respiration, the relationship of the apparent molecular weight conversion to a subsequent physiological event remains unclear.
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PMID:A peptide associated with eggs causes a mobility shift in a major plasma membrane protein of spermatozoa. 615 45

1. The effects of sodium nitroprusside (SNP, a nitric oxide donor) and authentic nitric oxide (NO) on superoxide anion (O2-) generation were investigated in human polymorphonuclear leukocytes (PMNs). 2. Neither SNP (10 nM to 10 microM) nor NO (40 nM to 40 microM) alone induced O2- generation or change of intracellular Ca2+ concentration ([Ca2+]i) in human PMNs. 3. Pretreatment with SNP or NO at the concentrations used (SNP, 10 nM to 10 microM: NO, 40 nM to 40 microM) showed a biphasic concentration-dependent effect on O2- generation induced by f-methionyl-leucyl-phenylalanine (FMLP). Low concentrations of SNP (10 nM to 100 nM) and NO (400 nM) did not affect either basal cyclic GMP levels or cyclic GMP levels stimulated by FMLP, but enhanced FMLP-induced O2- generation and [Ca2+]i elevation. On the other hand, high concentrations of SNP (10 microM) and NO (40 microM) alone elevated cyclic GMP levels and inhibited FMLP-induced O2- generation and [Ca2+]i elevation. 4. 8-Bromo-cyclic GMP (8-Br-cyclic GMP) at concentrations ranging from 1 microM to 1 mM did not induce O2- generation on its own and had little effect on FMLP-induced O2- generation and [Ca2+]i elevation. 5. Addition of a high concentration of NO (40 microM) decreased authentic O2- formation by pyrogallol in a cell-free system, but a low concentration of NO (400 nM) had no effect on this. On the other hand, addition of SNP in the concentration-ranges used had no effect on authentic O2- formation by pyrogallol. 6. In this study, we have shown that SNP and NO have dual effects (enhancement and inhibition) on 02- generation induced by FMLP in human peripheral PMNs. The results suggest that the enhancement observed with SNP and NO at low concentrations is not mediated by activation of the guanylate cyclase-cyclic GMP pathway. The suppressive effect of SNP and NO at higher concentrations is mediated by the NO-induced O2--scavenging effect and activation of the guanylate cyclase-cyclic GMP pathway.
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PMID:Enhancing and inhibitory effects of nitric oxide on superoxide anion generation in human polymorphonuclear leukocytes. 758 60

Products released through the L-arginine/nitric oxide biosynthetic pathway regulate soluble guanyl cyclase activity, which in turn modulates polymorphonuclear leukocyte chemotaxis. We hypothesized that inhibitors of nitric oxide synthase attenuate polymorphonuclear leukocyte chemotaxis in vitro. To test this hypothesis, unstimulated polymorphonuclear leukocytes were pretreated with buffer or the nitric oxide synthase inhibitors NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester, and L-canavanine before being exposed to three structurally unrelated chemoattractants, N-formyl-methionyl-leucyl-phenylalanine, C5a des arginine, and leukotriene B4. Polymorphonuclear leukocyte chemotaxis was quantified with a modified blind-well chamber technique. We found that L-NMMA and L-canavanine but not NG-nitro-L-arginine significantly attenuated polymorphonuclear leukocyte chemotaxis (p < 0.05). L-Arginine but not D-arginine, the nitric oxide donor sodium nitroprusside, and 8-bromo-cyclic guanosine monophosphate restored polymorphonuclear leukocyte chemotaxis attenuated by L-NMMA. Chemotaxis of polymorphonuclear leukocytes primed with lipopolysaccharide (Escherichia coli 0127:B8) or phorbol-13-butyrate was also significantly attenuated by pretreatment with L-NMMA and L-canavanine. Consistent with these observations, intracellular concentrations of cyclic guanosine monophosphate in polymorphonuclear leukocytes was decreased by L-NMMA during exposure to N-formyl-methionyl-leucyl-phenylalanine. These data indicate that nitric oxide synthase inhibitors attenuate chemotaxis of unstimulated and primed polymorphonuclear leukocytes in vitro. We suggest that the L-arginine/nitric oxide biosynthetic pathway plays an important role in regulating polymorphonuclear leukocyte emigration in vivo.
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PMID:Inhibitors of nitric oxide synthase attenuate human neutrophil chemotaxis in vitro. 769 39

The receptor for the Escherichia coli heat-stable enterotoxin has been characterized and partially purified from the T84 human colonic cell line. Using a novel mutant heat-stable enterotoxin peptide as a radioligand (the C-terminal tyrosine residue is replaced by phenylalanine in the mutant), a single class of high-affinity receptor sites was detected in T84 cells, with a Kd of 0.1 nM, similar in affinity to the receptor described in human intestinal tissue. The receptor was solubilised from T84 cell membranes and affinity cross-linking of the solubilised preparation indicated that a single species of M(r) 160,000 served as the receptor. Freshly solubilised preparations of the receptor retained heat-stable enterotoxin-activable guanylyl cyclase activity. Purification of the receptor was achieved through sequential affinity chromatography on GTP--epoxy-Sepharose and wheat-germ-agglutinin columns resulting in purification of the receptor by 3000 fold. The heat-stable enterotoxin-binding characteristics of the receptor were unchanged during the purification and silver staining of the purified receptor preparation indicated a band of M(r) 160,000, which was specifically cross-linked to the 125I-labeled mutant peptide. The purified receptor retained guanylyl cyclase activity, but the activity was not stimulated on addition of human heat-stable enterotoxin, suggesting that accessory structural factors may be involved in the activation of the guanylyl cyclase/receptor.
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PMID:Characterization and partial purification of the human receptor for the heat-stable enterotoxin. 790 48


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