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 second messengers cAMP and inositol-1,4,5-triphosphate have been implicated in olfaction in various species. The odorant-induced cGMP response was investigated using cilia preparations and olfactory primary cultures. Odorants cause a delayed and sustained elevation of cGMP. A component of this cGMP response is attributable to the activation of one of two kinetically distinct cilial receptor guanylyl cyclases by calcium and a guanylyl cyclase-activating protein (GCAP). cGMP thus formed serves to augment the cAMP signal in a cGMP-dependent protein kinase (PKG) manner by direct activation of adenylate cyclase. cAMP, in turn, activates cAMP-dependent protein kinase (PKA) to negatively regulate guanylyl cyclase, limiting the cGMP signal. These data demonstrate the existence of a regulatory loop in which cGMP can augment a cAMP signal, and in turn cAMP negatively regulates cGMP production via PKA. Thus, a small, localized, odorant-induced cAMP response may be amplified to modulate downstream transduction enzymes or transcriptional events.
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PMID:Calcium-sensitive particulate guanylyl cyclase as a modulator of cAMP in olfactory receptor neurons. 954 28

Vasoactive intestinal peptide (VIP) causes relaxation of smooth muscle cells via both VIP-specific receptor coupled to nitric oxide synthase and VIP-preferring receptor coupled to adenylate cyclase. Because the mechanism of interaction among VIP, pituitary adenylate cyclase-activating peptide (PACAP), and PTH is still unclear, the characteristics of the receptors for PACAP and PTH in circular muscle cells obtained from the guinea pig cecum were investigated. The effects of an inhibitor of cAMP-dependent protein kinase [cyclic adenosine 3',5'-monophosphorothioate (Rp-cAMPS)], guanylate cyclase inhibitors, antagonists of these peptides, and the selective receptor protection on the relaxing effect produced by PACAP, VIP, and PTH were examined. PACAP-induced relaxation was significantly inhibited by a VIP antagonist, a PTH antagonist, Rp-cAMPS, and an inhibitor of particulate guanylate cyclase. VIP-induced relaxation was significantly inhibited by a PACAP antagonist and a PTH antagonist. PTH-induced relaxation was significantly inhibited by a VIP-specific receptor antagonist and Rp-cAMPS, but not by a PACAP antagonist. A PTH antagonist significantly inhibited a VIP-preferring receptor agonist-induced relaxation. The muscle cells in which cholecystokinin octapeptide and PTH receptors were protected completely abolished the inhibitory responses to VIP and PACAP. The muscle cells in which cholecystokinin octapeptide and VIP or PACAP receptors were protected completely abolished the inhibitory response to PTH. This study shows that PACAP induces relaxation of these muscle cells via both VIP-preferring receptor coupled to adenylate cyclase and PACAP-specific receptor, and that PTH induces relaxation of the muscle cells via PTH-specific receptor coupled to adenylate cyclase. In addition, the results of a selective receptor protection show that PTH does not bind to VIP receptors, and that VIP does not bind to PTH receptor. Therefore, this study first demonstrates the presence of one-way inhibitory mechanisms from the PTH-specific receptor to the VIP-preferring receptor, and from the VIP-specific receptor to the PTH-specific receptor in the mechanisms of interaction between VIP and PTH.
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PMID:Interactive mechanisms among pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide, and parathyroid hormone receptors in guinea pig cecal circular smooth muscle cells. 960 96

We previously described the isolation of a variant subline of HL-60 cells that does not differentiate in response to nitric oxide (NO)-generating agents or to cGMP analogs. The variant cells have normal guanylate cyclase activity and normal NO-induced increases in the intracellular cGMP concentration. We now show that the variant cells have normal cGMP-dependent protein kinase (G-kinase) activity, both by an in vitro and in vivo assay, and using two-dimensional gel electrophoresis we have identified six G-kinase substrates in the parental cells. Of these six proteins, we found considerably less phosphorylation of one of the proteins in the variant cells than in parental cells, both in vitro and in intact cells, and by 35S-methionine/35S-cysteine incorporation we found much less of this protein in the variant cells than in parental cells. The protein is a shared substrate of cAMP-dependent protein kinase (A-kinase); since cAMP analogs still induce differentiation of the variant cells, it appears that the NO/cGMP/G-kinase and cAMP/A-kinase signal transduction pathways share some but not all of the same target proteins in inducing differentiation of HL-60 cells.
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PMID:Decreased phosphorylation of a low molecular weight protein by cGMP-dependent protein kinase in variant HL-60 cells resistant to nitric oxide- and cGMP-induced differentiation. 974 17

Calcitonin gene-related peptide (CGRP) plays a significant role in the non-adrenergic non-cholinergic (NANC) regulation of intestinal tract motility. In this work, the contractile properties of enzymatically isolated circular smooth muscle cells (SMC) from human colon in response to CGRP were evaluated. Relaxation by CGRP (1 microM) was determined in cells maximally contracted by carbachol (CCh, 1 nM). Simultaneously, cGMP contents of SMC were measured by radioimmunoassay. CCh-induced contraction was inhibited by 1 microM CGRP (maximum: 69+/-5% within 60 sec); similarly, exposure of cells to sodium nitroprussiate (SNP), 1 microM, fully inhibited contraction (maximum: 89+/-8% within 30 sec). In the same time-course as for relaxation, CGRP and sodium nitroprussiate caused significant increase in intracellular cGMP levels (2- and 10-fold that of the basal level, respectively, P < 0.01). The nitric oxide synthase (NOS) inhibitor, L-N5(I-iminoethyl)ornithine, dihydrochloride, (L-NIO), 1 microM, partly inhibited SMC relaxation induced by CGRP (78.26%); the protein kinase inhibitor, N-(2-aminoethyl)-5-isoquinolinesulfonamide hydrochloride (H9), 1 microM, and the selective cAMP-dependent protein kinase inhibitor, adenosine-3',5'-monophosphorothioate triethylammonium salt, Rp isomer, (Rp-cAMP(S)), 1 microM, also caused inhibition of relaxation (70.30% and 28.6%, respectively). In parallel, the increase in cGMP caused by CGRP was partly reduced by L-NIO (65.47%) and by H9 (55%). In conclusion, the nitric oxide generation following exposure of human colonic SMC to sodium nitroprussiate causes relaxation through the cGMP pathway; on the other hand, exposure of SMC to CGRP causes relaxation in part by activation of nitric oxide synthase and guanylate cyclase and in part through the cAMP pathway.
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PMID:Calcitonin gene-related peptide-induced relaxation of isolated human colonic smooth muscle cells through different intracellular pathways. 980 18

Nitric oxide (NO) regulates the expression of multiple genes but in most cases its precise mechanism of action is unclear. We used baby hamster kidney (BHK) cells, which have very low soluble guanylate cyclase and cGMP-dependent protein kinase (G-kinase) activity, and CS-54 arterial smooth muscle cells, which express these two enzymes, to study NO regulation of the human fos promoter. The NO-releasing agent Deta-NONOate (ethanamine-2,2'-(hydroxynitrosohydrazone)bis-) had no effect on a chloramphenicol acetyltransferase (CAT) reporter gene under control of the fos promoter in BHK cells transfected with an empty vector or in cells transfected with a G-kinase Ibeta expression vector. In BHK cells transfected with expression vectors for guanylate cyclase, Deta-NONOate markedly increased the intracellular cGMP concentration and caused a small (2-fold) increase in CAT activity; the increased CAT activity appeared to be from cGMP activation of cAMP-dependent protein kinase. In BHK cells co-transfected with guanylate cyclase and G-kinase expression vectors, CAT activity was increased 5-fold in the absence of Deta-NONOate and 7-fold in the presence of Deta-NONOate. Stimulation of CAT activity in the absence of Deta-NONOate appeared to be largely from endogenous NO since we found that: (i) BHK cells produced high amounts of NO; (ii) CAT activity was partially inhibited by a NO synthase inhibitor; and (iii) the inhibition by the NO synthase inhibitor was reversed by exogenous NO. In CS-54 cells, we found that NO increased fos promoter activity and that the increase was prevented by a guanylate cyclase inhibitor. In summary, we found that NO activates the fos promoter by a guanylate cyclase- and G-kinase-dependent mechanism.
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PMID:Nitric oxide regulation of gene transcription via soluble guanylate cyclase and type I cGMP-dependent protein kinase. 1009 32

Cell injury frequently occurs in the setting of tissue destruction and inflammation and is associated with a rise in intracellular calcium (Cai) and increased NO production. The mechanisms that trigger rises in Cai and NO during cell injury are not fully defined, but they may involve activation of G protein-coupled receptors for substances such as bradykinin, Ang II, thromboxane, and thrombin. These receptors act through G proteins from different families that have distinct functions. Receptors for bradykinin and Ang II act through members of the G alpha i and G alpha q families, whereas receptors for thrombin and thromboxane act through members of the G alpha i, G alpha q, and G alpha 12/13 families. These G proteins cooperate to regulate Cai and NO in epithelial cells through distinct mechanisms. In a number of experimental settings, activators of the adenylyl cyclase system reduce the severity of cell injury. To understand the mechanisms by which G protein-dependent signaling systems may contribute to cell injury and to define the role of adenylyl cyclase in ameliorating cell injury, the effects of adenylyl cyclase on bradykinin-stimulated Ca influx and NO in cultured renal epithelial cells that stably overexpress G alpha q and G alpha 13 were studied. This system allowed for the separation of different components of the signals initiated by receptors for thromboxane and thrombin. G alpha 13 increased bradykinin-stimulated Ca influx by a mechanism that depends on NO and cGMP. The increased Ca influx was blocked by inhibitors of NO synthase and guanylyl cyclase and by activation of adenylyl cyclase. NO production was inhibited by activators of cAMP-dependent protein kinase, which indicated that cAMP blocks Ca influx by inhibiting NO production. Expression of G alpha q, the G protein that regulates phospholipase C, also increased bradykinin-stimulated Ca influx, but by an NO, cGMP-independent mechanism that was insensitive to inhibition by adenylyl cyclase. The authors conclude that Ca influx is modulated by NO-dependent and independent mechanisms, and that to the extent that increased NO production contributes to increased Ca influx and cell injury, cell injury may be reduced by agents that activate adenylyl cyclase.
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PMID:Inhibition of nitric oxide synthase activity and nitric oxide-dependent calcium influx in renal epithelial cells by cyclic adenosine monophosphate: implications for cell injury. 1049 85

Long-term potentiation (LTP) in the hippocampus has an early phase (E-LTP) that can be induced by one- or two-train tetanization, lasts approximately 1 hr, and is cAMP-dependent protein kinase (PKA) and protein synthesis independent and a late phase (L-LTP) that can be induced by three- or four-train tetanization, lasts >3 hr, and is reduced by inhibitors of PKA and of protein or RNA synthesis. Nitric oxide (NO) is thought to be involved in E-LTP, but until now there has been no information about the role of the NO-signaling pathway in L-LTP. We examined this question at the Schaffer collateral-CA1 synapses in slices of mouse hippocampus. An inhibitor of NO synthase blocked L-LTP induced by three-train tetanization and reduced L-LTP induced by four-train tetanization, whereas an inhibitor of PKA was more effective in blocking four-train L-LTP than three-train L-LTP. Three-train L-LTP was also blocked by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase (PKG). Conversely, either NO or cGMP analogs paired with one-train tetanization produced late-phase potentiation, and the cGMP-induced potentiation was blocked by inhibitors of protein or RNA synthesis and an inhibitor of PKG, but not by an inhibitor of PKA. To test a possible downstream target of PKG, we examined changes in phospho-CRE-binding protein (phospho-CREB) immunofluorescence in the CA1 cell body area and obtained results similar to those of the electrophysiology experiments. These results suggest that NO contributes to L-LTP by stimulating guanylyl cyclase and cGMP-dependent protein kinase, which acts in parallel with PKA to increase phosphorylation of the transcription factor CREB.
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PMID:Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. 1057 22

1. Intracellular calcium concentration ([Ca2+]i) was measured in mouse whole islets of Langerhans using the calcium-sensitive fluorescent dye Indo-1. 2. Application of physiological concentrations of 17beta-oestradiol in the presence of a stimulatory glucose concentration (8 mM) potentiated the [Ca2+]i signal in 83 % of islets tested. Potentiation was manifested as either an increase in the frequency or duration of [Ca2+]i oscillations. 3. The effects caused by 17beta-oestradiol were mimicked by the cyclic nucleotide analogues 8-bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP). 4. Direct measurements of both cyclic nucleotides demonstrated that nanomolar concentrations of 17beta-oestradiol in the presence of 8 mM glucose increased cGMP levels, yet cAMP levels were unchanged. The increment in cGMP was similar to that induced by 11 mM glucose. 5. Patch-clamp recording in intact cells showed that 8-Br-cGMP reproduced the inhibitory action of 17beta-oestradiol on ATP-sensitive K+ (KATP) channel activity. This was not a membrane-bound effect since it could not be observed in excised patches. 6. The action of 17beta-oestradiol on KATP channel activity was not modified by the specific inhibitor of soluble guanylate cyclase (sGC) LY 83583. This result indicates a likely involvement of a membrane guanylate cyclase (mGC). 7. The rapid decrease in KATP channel activity elicited by 17beta-oestradiol was greatly reduced using Rp-8-pCPT-cGMPS, a specific blocker of cGMP-dependent protein kinase (PKG). Conversely, Rp-cAMPS, which inhibits cAMP-dependent protein kinase (PKA), had little effect. 8. The results presented here indicate that rapid, non-genomic effects of 17beta-oestradiol after interaction with its binding site at the plasma membrane of pancreatic beta-cells is a cGMP-dependent phosphorylation process.
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PMID:Non-genomic actions of 17beta-oestradiol in mouse pancreatic beta-cells are mediated by a cGMP-dependent protein kinase. 1058 11

Although odorants are known to activate olfactory receptor neurons through cAMP, the long-term effects of odorant detection are not known. Our recent findings indicate that there is also a delayed and sustained cAMP response, with kinetics sufficient to mediate long-term cellular responses. This cAMP response is mediated by cGMP through activation of adenylyl cyclase by protein kinase G (PKG). Therefore, we investigated the ability of odorants to regulate gene expression in rat olfactory epithelium. The cAMP-responsive binding protein (CREB) is a well-characterized transcription factor regulated by cAMP. We examined CREB activity in rat olfactory epithelium and olfactory receptor neurons (ORNs) after stimulation with odorants. Odorants increased levels of phosphorylated CREB in olfactory epithelium in vivo, and this increase was localized to ORNs in vitro. Incubation with 8-bromo-cGMP or sodium nitroprusside, a guanylyl cyclase activator, also increased phosphorylated CREB. In vitro, cAMP-dependent protein kinase phosphorylated CREB. In contrast, PKG failed to phosphorylate CREB directly in vitro. Our results demonstrate that the delayed odorant-induced cAMP signal activates CREB, which in turn may modulate gene expression in ORNs. In addition, cGMP indirectly affects CREB activation. This effect of cGMP on CREB activity through cAMP provides another mechanism for the modulation of CREB.
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PMID:Odorants induce the phosphorylation of the cAMP response element binding protein in olfactory receptor neurons. 1058 52

Guinea pig caecal circular smooth muscle cells were used to determine whether brain natriuretic peptide (BNP) can inhibit the contractile response produced by cholecystokinin-octapeptide (CCK-8). In addition, we examined the effect of an inhibitor of cAMP-dependent protein kinase, an inhibitor of particulate or soluble guanylate cyclase, an atrial natriuretic peptide (ANP) antagonist (ANP 1-11), and selective receptor protection on the BNP-induced relaxation of these muscle cells. The effect of BNP on cAMP formation was also examined. BNP inhibited the contractile response produced by CCK-8 in a dose-response manner, with an IC50 value of 8.5 nM, and stimulated the production of cAMP. The inhibitor of cAMP-dependent protein kinase and the inhibitor of soluble guanylate cyclase significantly inhibited the relaxation produced by BNP. In contrast, the inhibitor of particulate guanylate cyclase did not have any significant effect on the relaxation produced by BNP. ANP 1-11 significantly but partially inhibited the relaxation produced by BNP. The muscle cells where CCK-8 and ANP binding sites were protected completely preserved the inhibitory response to ANP, but partially preserved the inhibitory response to BNP. The muscle cells where CCK-8 and BNP binding sites were protected completely preserved the inhibitory response to both ANP and BNP. This study demonstrates that BNP induces relaxation of these muscle cells via both ANP binding sites coupled to soluble guanylate cyclase and distinct BNP binding sites coupled to adenylate cyclase.
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PMID:Interaction between brain natriuretic peptide and atrial natriuretic peptide in caecal circular smooth muscle cells. 1067 11


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