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)

1. Full inhibition of thrombin-induced platelet aggregation was elicited by the least maximal platelet inhibitory concentrations of nitric oxide (NO; 7 +/- 1 microM) or NO-donors which included sodium nitroprusside (NaNp; 80 +/- 13 microM) 3-morpholinosydnonimine (SIN-1; 3 +/- 0.1 microM) or endothelial cells (EC; 2.36 +/- 0.12 x 10(5) added 1 min before thrombin. Oxyhaemoglobin (oxyHb; 10 microM) administered 30s to 10 min after stimulation with thrombin caused a time-dependent reversal of the inhibition induced by these agents. OxyHb was ineffective when these agents were co-incubated with the non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 0.05 mM). 2. OxyHb did not reverse the platelet inhibition with IBMX (0.2 mM) or that caused by a selective guanosine 3'; 5'-cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor 2-O-propoxyphenyl-8-azapurin-6-one, (M & B 22948; 20 microM). In addition, oxyHb did not reverse the inhibition with iloprost (1 nM) which inhibits platelet aggregation through stimulation of adenylate cyclase. 3. The inhibition of platelet aggregation by NO (7 +/- 1 microM) or NaNp (80 +/- 13 microM) was accompanied by a 13 fold increase in cyclic GMP levels occurring within 15 s of addition of these agents. In the continued presence of NO or NaNp, the reversing effect of oxyHb given 1 min after thrombin was associated with a pronounced decrease in cyclic GMP levels. 4. We conclude that the inhibition of platelet aggregation by activators of guanylate cyclase depends in the first few minutes on continuous stimulation of the enzyme in order to maintain intracellular concentrations of cyclic GMP, except when its breakdown is inhibited. 5. The addition of agents such as oxyHb after the inhibition of platelet aggregation offers another way of investigating the biochemical changes involved in maintaining platelets in an inactive state.
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PMID:The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO-donors. 170 9

Estrogen-induced protein was purified from rat uteri and assayed for several enzymatic activities involved in the metabolism and action of cyclic nucleotides. No adenylate and guanylate cyclase (EC 4.6.1.1 and 4.6.1.2, respectively), protein kinase (EC 2.7.1.33), and cyclic nucleotide binding activities could be demonstrated in three independent preparations of the protein. However, all three preparations exhibited significant phosphoprotein phosphatase activity (EC 3.1.3.16) on phosphorylated protamine and histones F1. This activity is optimal at neutral pH, inhibited by Zn(++), and unaffected by cyclic AMP or cyclic GMP.
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PMID:Phosphoprotein phosphatase activity associated with estrogen-induced protein in rat uterus. 415 69

The need for nonshivering heat production, a principal function of brown adipose tissue, is accentuated in neonates. Accordingly, brown fat in the rat exhibits a very pronounced process of morphological and functional maturation perinatally, reaches a peak in its differentiation and heat-generating capacity within 1-2 weeks after birth, and undergoes involutive changes later in life. The later process of dedifferentiation can be either prevented or reversed by exposing the animals to cold ambient temperature for a prolonged period of time (cold acclimatization). The regulation of both the tissue maturation processes and the superimposed acute heat production are hormone mediated. Thus, the hormone receptor system within the adipocyte membrane and the sequence of molecular events interconnecting the initial hormonal stimulus with its final intracellular effect(s) are of considerable importance. The brown adipocytes of developing rats possess adrenoreceptors that can be pharmacologically classified as beta 1 (linked to adenylate cyclase) and alpha 2 (possibly linked to guanylate cyclase), multiple forms of cyclic nucleotide dependent and independent protein kinases, a protein kinase inhibitor, and at least two distinct phosphoprotein phosphatases associated with three phosphoprotein phosphatase modulators. The characteristics and developmental alterations of these regulatory components were studied in considerable detail by our group during the past decade. The results uncovered several target systems for ontogenic modifications of hormonal responses. Strong support was obtained for the hypothesis that protein phosphorylation and dephosphorylation is a major molecular mechanism involved in the regulation of both the brown adipocyte function and its proliferative activity during ontogenic development.
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PMID:Mechanisms of hormonal regulations in brown adipose tissue of developing rats. 614 37

In this study, we hypothesized that histaminergic increases in venular permeability result from a cascade triggered by activation of phospholipase C (PLC), inducing the synthesis of nitric oxide (NO) and activating guanylate cyclase. The apparent permeability coefficient to albumin (Pa) was measured in isolated porcine coronary venules subjected to constant flow and hydrostatic and oncotic pressures. Histamine (2.5, 5, and 10 microM) transiently and progressively increased Pa. The PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC; 100 microM) decreased baseline permeability and abolished the effect of histamine. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10 microM) and the guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY 83583; 10 microM) also blocked the histamine-induced hyperpermeability. L-Arginine (3 mM) reversed the inhibition by L-NMMA. NG-monomethyl-D-arginine did not influence the effect of histamine. Furthermore, sodium nitroprusside (10 microM) augmented Pa by two- to threefold; this effect was blocked in the presence of LY 83583 but not altered in the presence of NCDC. The results suggest that histamine increases coronary venular permeability by a direct action on the venular endothelial cells through a PLC-NO synthase-guanylate cyclase-signaling cascade.
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PMID:Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. 768 77

Eosinophil migration in vivo is markedly attenuated in rats treated chronically with the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). In this study, we investigated the existence of a NOS system in eosinophils. Our results demonstrated that rat peritoneal eosinophils strongly express both type II (30.2 +/- 11.6% of counted cells) and type III (24.7 +/- 7.4% of counted cells) NOS, as detected by immunohistochemistry using affinity purified mouse mAbs. Eosinophil migration in vitro was evaluated by using 48-well microchemotaxis chambers and the chemotactic agents used were N-formyl-methionyl-leucyl-phenylalanine (fMLP, 5 x 10(-8) M) and leukotriene B4 (LTB4, 10(-8) M). L-NAME (but not D-NAME) significantly inhibited the eosinophil migration induced by both fMLP (54% reduction for 1.0 mM; P < 0.05) and LTB4 (61% reduction for 1.0 mM; P < 0.05). In addition, the type II NOS inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine and the type I/II NOS inhibitor 1-(2-trifluoromethylphenyl) imidazole also markedly (P < 0. 05) attenuated fMLP- (52% and 38% reduction for 1.0 mM, respectively) and LTB4- (52% and 51% reduction for 1.0 mM, respectively) induced migration. The inhibition of eosinophil migration by L-NAME was mimicked by the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a] quinoxalin-1-one (0.01 and 0.1 mM) and reversed by either sodium nitroprusside (0.1 mM) or dibutyryl cyclic GMP (1 mM). We conclude that eosinophils do express NO synthase(s) and that nitric oxide plays an essential role in eosinophil locomotion by acting through a cyclic GMP transduction mechanism.
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PMID:Pharmacological and immunohistochemical evidence for a functional nitric oxide synthase system in rat peritoneal eosinophils. 939 Nov 61

Matrix metalloproteinases (MMPs) are synthesized in response to diverse stimuli, including cytokines, growth factors, hormones, and oxidative stress. Here we show that the nitric oxide (NO) donor 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO) and NO from murine macrophages transcriptionally regulate MMP-13 expression in vascular endothelial cells (BAEC). The cGMP analog, 8-bromo-cGMP (8-Br-cGMP) mimicked the effect of NO, whereas incubation with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or the cGMP-dependent protein kinase (PKG) inhibitor phenyl-1,N (2)- etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (PET) reduced the stimulatory effect of DEA-NO on the activation of the MMP-13 promoter. Overexpression of the catalytic subunit of PKG1-alpha resulted in a 5- to 6-fold increase of the MMP-13 regulatory region over control cells. On the other hand, incubation with the mitogen-activated protein/extracellular signal-regulated kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) significantly reduced DEA-NO and 8-Br-cGMP promoter activation and mRNA expression of MMP-13 in transfected BAEC. Moreover, a complex between PKG1-alpha and the G-protein Raf-1, an upstream activator of the extracellular signal-regulated kinase signaling pathway, was detected in cells overexpressing PKG1-alpha or treated either with DEA-NO or 8-Br-cGMP. Thus, we propose that the NO-cGMP-PKG pathway enhances MMP-13 expression by the activation of ERK 1,2. This effect of NO may be important in the context of pathophysiological conditions such as inflammation or atherogenesis [corrected].
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PMID:Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells. 1223 40

Nitric oxide (NO) is known to affect synaptic plasticity in various regions of the brain via the cGMP-cGMP-dependent protein kinase (PKG) pathway. We found that a novel compound 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole (YC-1), a drug known to modulate the response of soluble guanylyl cyclase to NO, greatly potentiates long-term potentiation (LTP). This compound markedly enhanced the induction of LTP in rat hippocampal and amygdala slices by weak tetanic stimulation. The potentiation of LTP by YC-1 was greatly reduced by NO synthase inhibitor Ng-nitro-l-arginine-methylester, guanylyl cyclase inhibitor 1 H-[1,2,4]-oxadiazolo(4,3-a)-quinoxalin-1-one, and PKG inhibitor (9S,10R,12R)-2,3,9,10,11,12, hexahydro-10-methoxy-2,9-dimethyl-1-ox0-9.12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT5823). In addition, mitogen-activated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) also markedly inhibited LTP potentiating action of YC-1. Intracellular increase of Ca2+ concentration derived from N-methyl-d-aspartate and glutamate metabotropic receptors contributes to the potentiating action of YC-1. Concurrent perfusion of YC-1 and NO donor sodium nitroprusside for a short time period resulted in the induction of LTP by stimuli at a frequency as low as 0.02 Hz. Incubation of unstimulated hippocampal slices with YC-1 plus nitroprusside increased the immunofluorescence of phospho-extracellular signal-regulated kinase (ERK) and phospho-cAMP response element binding protein (CREB). Furthermore, the Western blot shows that the phosphorylation of ERKs 1 and 2 and CREB of unstimulated hippocampal slices was increased by YC-1 plus nitroprusside, which was inhibited by KT5823. The NO-cGMP-PKG-ERK signaling pathway thus plays important role in the potentiation of LTP by YC-1.
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PMID:Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. 1276 28

Nitric oxide synthase (NOS) isoforms and NO downstream signal pathways involved spinally in the maintenance of thermal and mechanical hypersensitivity were assessed in a mouse model of neuropathic pain developing after partial ligation of the sciatic nerve. Intrathecal injection of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME), the highly selective neuronal NOS (nNOS) inhibitor N(omega)-propyl-l-arginine and the potent selective inducible NOS (iNOS) inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine hydrochloride (AMT) exerted dose-dependent analgesic effects on thermal and mechanical hypersensitivity, which were assessed by the plantar and von Frey tests, respectively, suggesting that both nNOS and iNOS participate in producing NO to maintain neuropathic pain. Since the selective inhibitor of NO-sensitive guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG) inhibitor Rp-8-pCPT-cGMPS intrathecally exerted dose-dependent analgesic effects on thermal and mechanical hypersensitivity, spinally released NO most likely stimulates the NO-cGMP-PKG pathway. Moreover, the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), a potent superoxide scavenger, reduced thermal and mechanical hypersensitivity when administered intrathecally, suggesting that spinal release of superoxide, which can then react with NO to produce peroxynitrite, also appears to mediate neuropathic pain. Finally, intrathecal injection of phenyl-N-tert-butylnitrone (PBN), a reactive oxygen species (ROS) scavenger, ameliorated thermal and mechanical hypersensitivity, thus further confirming the importance of ROS including NO and superoxide in the maintenance of neuropathic pain. Together, the present results demonstrate that NO, produced presumably via nNOS and iNOS in the spinal cord, mediates the maintenance of neuropathic pain following peripheral nerve injury through both the NO-cGMP-PKG and the NO-peroxynitrite pathways.
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PMID:Pharmacological assessments of nitric oxide synthase isoforms and downstream diversity of NO signaling in the maintenance of thermal and mechanical hypersensitivity after peripheral nerve injury in mice. 1911 53

VILIP-1 (visinin-like protein 1) is downregulated in various human squamous cell carcinoma (SCC). In a mouse skin SCC model VILIP-1 expression is reduced in aggressive tumor cells, accompanied by reduced cAMP levels. Overexpression of VILIP-1 in aggressive SCC cells led to enhanced cAMP production, in turn causing a reduction in invasive properties. Moreover, in primary neurons and neuronal tumor lines VILIP-1 enhanced cGMP signaling. Here, we set out to determine whether and how cAMP and cGMP signaling contribute to the VILIP-1 effect on enhanced SCC model cell migration, and thus most likely invasiveness in vivo. We found stronger increase in cGMP levels in aggressive, VILIP-1-negative SCC cells following stimulation of guanylyl cyclases NPR-A and -B with the natriuretic peptides ANP and CNP, respectively. Incubation with ANP or 8Br-cGMP to increase cGMP levels further enhanced the migration capacity of aggressive cells, whereas cell adhesion was unaffected. Increased cGMP was caused by elevated expression levels of NPR-A and -B. However, the expression level of VILIP-1 did not affect cGMP signaling and guanylyl cyclase expression in SCC. In contrast, VILIP-1 led to reduced migration of aggressive SCC cells depending on cAMP levels as shown by use of adenylyl cyclase (AC) inhibitor 2',3'-dideoxyadenosine. Involvement of cAMP-effectors PKA and EPAC play a role downstream of AC activation. VILIP-1-positive and -negative cells did not differ in mRNA expression of ACs, but an effect on enhanced protein expression and membrane localization of ACs was shown to underlie enhancement of cAMP production and, thus, reduction in cell migration by VILIP-1.
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PMID:Involvement of VILIP-1 (visinin-like protein) and opposite roles of cyclic AMP and GMP signaling in in vitro cell migration of murine skin squamous cell carcinoma. 2148 Mar 86

The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.
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PMID:The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells. 2167 83


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