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)

In the testis the mesenchymally derived peritubular cells produce a paracrine factor, PModS, that mediates mesenchymal-epithelial interactions and modulates Sertoli cell functions essential for the process of spermatogenesis. PModS has a more dramatic effect on Sertoli cell differentiated functions in vitro than any regulatory agent previously shown to influence the cells, including FSH. The current study initiates an investigation of the pharmacology of PModS through an analysis of several common signal transduction pathways. PModS was found to stimulate cGMP levels in Sertoli cells and maintain elevated levels for up to 5 days in culture. PModS had no influence on cAMP levels. In contrast, FSH stimulated cAMP, but had no influence on cGMP levels. For comparison, an agent known to influence cGMP levels, atrial naturetic factor (ANF), was used to treat Sertoli cells. ANF caused a dramatic increase in Sertoli cell cGMP levels within minutes of treatment, but did not maintain elevated cGMP levels after a 72-h treatment. Although ANF increased guanylate cyclase in whole Sertoli cell homogenates and particulate fractions, PModS did not directly influence guanylate cyclase activity. As previously shown, PModS stimulates transferrin expression as a marker of Sertoli cell differentiated function. Agents that elevate cellular cGMP, including ANF, sodium nitroprusside, and 8-bromo-cGMP, did not influence Sertoli cell transferrin expression. In addition, these agents did not influence the actions of PModS or FSH. Therefore, cGMP does not appear to directly mediate the actions of PModS. As an alternative signal transduction pathway, calcium mobilization and inositol phosphate (IP) metabolism were examined. PModS did not alter calcium uptake or intracellular calcium mobilization. PModS also did not influence the levels of inositol mono-, bis-, or trisphosphates, whereas calf serum did stimulate levels of all three IP metabolites in Sertoli cells. Therefore, PModS does not appear to act through a mobilization of calcium or increased metabolism of IP. A final signal transduction pathway involving phosphorylation was also examined. PModS treatment was found to increase tyrosine phosphorylation of specific proteins in a crude Sertoli cell cytosol preparation. Genistein is an inhibitor of tyrosine kinases and was found to reduce PModS actions at a 3.7-microM concentration of genistein and inhibit PModS actions at a 37-microM concentration of genistein. Therefore, PModS may act through a tyrosine phosphorylation event that remains to be elucidated. Combined observations indicate that PModS does not use cyclic nucleotides, calcium mobilization, or IP metabolism as a signal transduction pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of Sertoli cell differentiation by the testicular paracrine factor PModS: analysis of common signal transduction pathways. 790 30

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

We examined the effects of C-type natriuretic peptide (CNP) on cyclic GMP production and catecholamine synthesis in cultured bovine adrenal medullary cells. 1) CNP increased intracellular cyclic GMP content in a concentration-dependent manner (10-1000 nM). 2) The cyclic GMP production induced by 1 microM CNP reached a 200-fold increase, and the effect of CNP was most potent among the natriuretic peptide family. 3) The CNP-induced cyclic GMP production was attenuated by endothelin (1 microM) and angiotensin II (0.1-1 microM). 4) When the cells were cultured with hypertonic NaCl medium, the CNP-induced cyclic GMP production was potentiated in a time (1-4 days)- and concentration (25-100 mM)-dependent manner. 5) CNP stimulated the synthesis of 14C-labeled catecholamines from [14C] tyrosine but not from [14C] dopa. The stimulatory effect of CNP on the 14C-labeled catecholamine synthesis was observed at the concentrations of 100 to 100 nM. 6) 8-Bromo cyclic GMP, a membrane-permeable cyclic GMP analog, and sodium nitroprusside, an activator of soluble guanylate cyclase, also stimulated the synthesis of 14C-labeled catecholamines from [14C]tyrosine, whereas C-ANF, a specific ligand for the ANP-C (clearance) receptor that does not increase cyclic GMP content, failed to stimulate the synthesis of 14C-labeled catecholamines. 7) CNP (1 microM) as well as 8-bromo cyclic GMP and sodium nitroprusside increased the activity of tyrosine hydroxylase in the cells. These results suggest that in the adrenal medulla, CNP is a potent agonist for cyclic GMP production, which is modulated by endothelin, angiotensin II and the hypertonic NaCl condition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:C-type natriuretic peptide stimulates catecholamine synthesis through the accumulation of cyclic GMP in cultured bovine adrenal medullary cells. 790 32

The cloning of particulate and soluble guanylyl cyclases is summarized in Table I. With respect to transmembrane signal transduction systems, guanylyl and adenylyl cyclases can be grouped together with some protein tyrosine kinases and protein tyrosine phosphatases to form a diverse protein family with various structural and functional similarities (Garbers, 1989, 1991, 1992; Koesling et al., 1991; Chinkers and Garbers, 1991; Fig. 1). Particulate guanylyl cyclase contains a single transmembrane domain, and the peptide-binding portion (ligand receptor) is on the exterior surface and the catalytic region on the interior, similar to the protein tyrosine kinase/receptor and the protein tyrosine phosphatase/receptor families (Yarden et al., 1986; Charbonneau et al., 1988; Tonks et al., 1988). Protein tyrosine kinases and phosphatases are also activated by ligand binding to the extracellular domain, which in turn results in phosphorylation or dephosphorylation. On the other hand, soluble guanylyl cyclase exists as a heterodimer with two putative catalytic domains, and both subunits are essential for enzyme activity and activation by nitric oxide. It is thus particularly interesting that adenylyl cyclase also contains two catalytic domains, which are both necessary for catalytic activity (Tang et al., 1991). It is possible that particulate guanylyl cyclase may also dimerize on hormonal stimulation and two catalytic domains from two monomers form a functional catalytic center capable of forming cyclic GMP. The catalytic core of GC-A expressed in bacteria was shown to form a homodimer with positively cooperative kinetics (Thorpe et al., 1991). The physiological significance of the existence of multiple forms of soluble guanylyl cyclase subunits remains unclear. Future studies should reveal the differences in tissue distribution and activation by nitrovasodilators in various heterodimers of soluble guanylyl cyclase.
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PMID:Cloning of guanylyl cyclase isoforms. 791 20

Tyrphostins are a group of organic compounds which are widely used as a tool to specifically inhibit protein tyrosine kinases (Yaish, P., Gazit, A., Gilon, C., and levitzki A. (1988) Science 242, 933-935; Gazit, A., Yaish, P., Gilon, C., and Levitzki A. (1989) J. Med. Chem. 32, 2344-2352; Lyall, R. M., Zilberstein, A., Gazit, A., Gilon, C., Levitzki, A., and Schlessinger J. (1989) J. Biol. Chem. 264, 14503-14509; Osherov, N., Gazit, A., Gilon, C., and Levitzki, A. (1993) J. Biol. Chem. 268, 11134-11142). We report here that members of the tyrphostin family inhibit the GTPase activity of transducin and the enzymatic activities of other GTP-utilizing proteins in retinal rod outer segments, such as guanylyl cyclase or fructose-6-phosphate kinase. In contrast, ATP-utilizing enzymes such as hexokinase or rhodopsin kinase were not effected.
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PMID:Inhibition of GTP-utilizing enzymes by tyrphostins. 791 15

Most of angiotensin II's (Ang II) documented effects have been attributed to the interaction of this peptide with a G-protein coupled receptor termed AT1. The role and the signalling mechanisms of the more recently characterized AT2 receptor, which does not appear to interact with G-proteins, are however still unclear. We report here that this receptor mediates the rapid dephosphorylation of tyrosine residues of specific proteins in the 60 to 150 KDa range in PC12W cells which express only AT2 receptors. We further characterized this phosphatase activity using the synthetic substrate para-nitrophenyl phosphate. Dephosphorylation of this substrate in response to Ang II is not affected by Ser/Thr phosphatase inhibitors, but is completely prevented by the protein tyrosine phosphatase (PTPase) inhibitor sodium orthovanadate. This effect is mimicked by the AT2 selective agonist CGP42112 and is not affected by the AT1 antagonist losartan, In contrast to the recently reported PTPase stimulation by somatostatin and dopamine, PTPase stimulation by Ang II is not affected by the guanyl nucleotides GTP gamma S and GDP beta S. Moreover, depletion of solubilized membrane preparations from G-proteins by lectin affinity chromatography does not alter Ang II stimulation of the measured PTPase activity. These findings indicate that Ang II stimulates a PTPase activity through AT2 receptors via G-protein independent pathways. This signalling mechanism may be involved in AT2 receptor mediated actions of Ang II such as particulate guanylate cyclase inhibition, modulation of T-type Ca++ channels and regulation of cell proliferation and differentiation.
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PMID:Angiotensin II stimulates protein tyrosine phosphatase activity through a G-protein independent mechanism. 795 93

Protein kinase-related domains of unknown function are present in the JAK family of protein tyrosine kinases and in receptor/guanylyl cyclases. I used the yeast two-hybrid system to screen for proteins interacting with the kinase-like domain of the atrial natriuretic peptide (ANP) receptor/guanylyl cyclase. A yeast strain was constructed expressing a fusion of this kinase-like domain to the lexA DNA-binding domain and containing a HIS3 gene under the control of lexA upstream activating sequences. These yeast cells were transformed with a plasmid library of mouse embryo cDNA fragments fused to the VP16 transcriptional activation domain. Cells containing VP16-fusion proteins interacting with the lexA-kinase-like domain fusion protein were selected by growth in the absence of histidine. A partial-length cDNA clone isolated by using this approach encoded a protein that interacted specifically with the ANP-receptor protein kinase-like domain both in yeast cells and in vitro. Tissue-specific expression of a 2.2-kb mRNA hybridizing to this cDNA paralleled the known pattern of ANP-receptor mRNA expression. A full-length cDNA clone isolated from a rat lung library was predicted to encode a 55-kDa protein containing at its amino terminus a targeting domain that binds to the ANP-receptor kinase-like domain and containing at its carboxyl terminus a putative protein-serine phosphatase domain. This protein is a possible candidate for the phosphatase involved in desensitizing the ANP receptor. Targeting of regulatory proteins may be an important function of protein kinase-like domains.
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PMID:Targeting of a distinctive protein-serine phosphatase to the protein kinase-like domain of the atrial natriuretic peptide receptor. 797 12

Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP)-activated guanylate cyclases are single-chain transmembrane-spanning proteins, containing both ligand binding and catalytic activities. In both proteins, ligand binding to the extracellular receptor domain activates the cytosolic catalytic domain, generating the second messenger cyclic GMP. Studies with ANF receptor guanylate cyclase (ANF-RGC) have indicated that obligatory in this activation process is an ATP-dependent step. ATP directly binds to the cyclase and bridges the events of ligand binding and signal transduction. A defined ATP-regulated module (ARM) sequence (Gly503-Arg-Gly-Ser-Asn-Tyr-Gly509) in the cyclase is critical in the ATP-mediated event. Through genetic remodeling techniques, we have now identified the core ARM sequence that is essential in both ANF and CNP signaling. This sequence is Gly-Xa-Xa-Xa-Gly, represented by Gly505-Ser-Asn-Tyr-Gly509 in the case of ANF-RGC ARM and by Gly499-Ser-Ser-Tyr-Gly503 in the CNP receptor guanylate cyclase ARM.
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PMID:Core sequence of ATP regulatory module in receptor guanylate cyclases. 809 55

Hyperplasia of the pancreatic tissue during late lactation (third week) and lasting for at least the first two weeks after weaning has been observed by several authors. Since the tetradecapeptide somatostatin (SS) inhibits pancreatic growth and its plasma levels are elevated during these periods, the aim of the present study was to determine the possible implication of the somatostatinergic system in the pancreatic changes cited above. Thus, the present study investigated 125I-Tyr(11)-somatostatin (125I-Tyr(11)-SS) binding and the effects of SS on guanylate cyclase activity as well as pancreatic somatostatin-like immunoreactivity (SSLI) levels in pancreatic acinar membranes from control, lactating and weaning rats. SS receptors were identified using 125I-Tyr(11)-SS and isolated pancreatic acinar membranes in vitro. There was an increase in the number of SS receptors after the third week of lactation (244 +/- 6 vs. 155 +/- 12 fmol/mg protein, P < 0.01) and the first two weeks after weaning (327 +/- 8 vs. 164 +/-10 fmol/mg protein, P < 0.001). No change in the affinity of the receptor site was detected at either study time. In addition, SS-stimulated guanylate cyclase activity was markedly increased at the third week of lactation (119%) and at the second week after weaning (158%) when compared with the control group. In contrast, basal guanylate cyclase activity was not modified at either study period. Thus, SS-stimulated guanylate cyclase activity is increased in pancreatic acinar membranes at late lactation and at the second week after beginning weaning probably due to an increase in the number of SS receptors. Significant decreases in SSLI content were observed at the third week of lactation (69%) and the second week after weaning (37%) when compared with the respective controls. The present results suggest that pancreatic acinar cell growth observed at the third week of lactation and the second week after weaning is associated with up-regulation of SS receptors which would represent a mechanism promoted by the cell that would negatively regulate the mitogenic activity of the increased number of pancreatic growth factors observed during both periods.
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PMID:Lactational changes in the rat exocrine pancreas somatostatin receptors and modulation of guanylate cyclase. 867 46

In order to provide further support for a role of central nitric oxide as a mediator of penile erection and yawning, the nitric oxide donors sodium nitroprusside, hydroxylamine, isoamyl nitrite and S-nitroso-N-acetyl-penicillamine were injected into the lateral ventricles (i.c.v.) or into the paraventricular nucleus of the hypothalamus of male rats. Of the above compounds injected i.c.v., only isoamyl nitrite (10-100 micrograms) induced penile erection and yawning, while the others induced dramatic behavioral changes, such as motor hyperactivity and convulsions, that masked the above responses. Nevertheless, nitric oxide donors in doses ranging from 10 to 50 micrograms, for except S-nitroso-N-acetyl-penicillamine that was injected only at the dose of 10 micrograms and isoamyl nitrite that was not injected at all because of poor solubility, induced penile erection and yawning when injected in the paraventricular nucleus. Nitric oxide donor-induced responses were prevented by methylene blue and LY 83583, inhibitors of guanylate cyclase, the best known target of nitric oxide, given i.c.v. but not in the paraventricular nucleus. However, 8-bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a stable cGMP analog, and hemoglobin, a nitric oxide scavenger, were ineffective in inducing and preventing, respectively, penile erection and yawning when injected either i.c.v. or in the paraventricular nucleus. Nitric oxide donor-induced responses were also prevented by the nonapeptide oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin given i.c.v. but not in the paraventricular nucleus. The present results suggest that nitric oxide donors induce penile erection and yawning by activating central oxytocinergic transmission in the paraventricular nucleus of the hypothalamus via a cGMP-independent mechanism.
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PMID:Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. 878 10


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