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)

Patients carrying mutations in the retinal guanylate cyclase (GUCY2D) gene were reported to be constantly affected with a particular form of Leber congenital amaurosis (LCA) defined as a "congenital stationary cone-rod dystrophy with high hypermetropia, panretinal degeneration and highly reduced visual acuity". We report here, the study of two patients affected with different retinal disorder: a typical GUCY2D-LCA phenotype and early-onset severe retinitis pigmentosa (RP). Unexpectedly, they gave birth to an infant suffering from LCA. The genetic study in the family allowed to explain the disease in the infant by showing that the GUCY2D-LCA disease was accounted for by compound heterozygosity for two severe GUCY2D mutations (c.3043+4A>T, c.2943delG) while the early-onset severe RP resulted from homozygosity for a 4 bp insertion in the same gene, despite the sound phenotypic differences (c.3236insACCA). Interestingly, this last mutation is excepted to result in a 28 amino acid elongation of the protein contrary to all GUCY2D mutations accounting for LCA which are expected to be null alleles. This report gives support to the existence of exceptional GUCY2D mutations accounting for a milder and different phenotype compared to the typical GUCY2D congenital stationary cone-rod dystrophy.
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PMID:A novel mutation in the GUCY2D gene responsible for an early onset severe RP different from the usual GUCY2D-LCA phenotype. 1564 14

The influence of nitric oxide (NO) on hypnotic activity of diazepam, chlordiazepoxide and clonazepam was studied in mice. Administration of both non-selective NO synthase inhibitors: N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-nitro-L-arginine (L-NOARG) and selective NO synthase inhibitor 7-nitroindazole (7-NI) resulted in significant increase in the duration of diazepam-, chlordiazepoxide- and clonazepam-induced sleep. The effects of co-administration of the examined inhibitors with benzodiazepines were not changed by L-arginine, a substrate for NO formation. Administration of L-arginine alone had no effect on the duration of sleep induced by benzodiazepines. Methylene blue, the guanyl cyclase inhibitor, was able to increase the duration of benzodiazepine-induced sleep. These findings suggest that the cGMP/NO system may participate in hypnotic effects of benzodiazepines.
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PMID:Involvement of nitricoxidergic system in the hypnotic effects of benzodiazepines in mice. 1566 84

The importance of the second messengers, Ca(2+) and cyclic GMP, for the process of fertilization is well established; the mechanisms for their intracellular regulations in the testes are, however, poorly understood. This study documents the biochemical, molecular, and functional identity of a Ca(2+)-modulated membrane guanylate cyclase transduction machinery in bovine testes. The machinery is both inhibited and stimulated by free Ca(2+) levels. The Ca(2+)-sensor component of the inhibitory mode of the machinery is GCAP1 (guanylate cyclase activating protein type 1) and for the stimulatory mode is S100B. The transduction component is a Ca(2+)-driven rod outer segment membrane guanylate cyclase type 1, ROS-GC1. The cyclase is predominantly expressed in spermatogenic cells. GCAP1 expression is restricted to a small population of spermatogonia, whereas S100B is present in the majority of spermatocytes and spermatids. The expression of GCAP1 and S100B in spermatocytes and spermatids is mutually exclusive.
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PMID:Calcium-modulated rod outer segment membrane guanylate cyclase type 1 transduction machinery in the testes. 1692 96

Large (pathological) amounts of nitric oxide (NO) induce cell injury, whereas low (physiological) NO concentrations often ameliorate cell injury. We tested the hypotheses that pretreatment of endothelial cells with low concentrations of NO (preconditioning) would prevent injury induced by high NO concentrations. Apoptosis, induced in bovine aortic endothelial cells (BAECs) by exposing them to either 4 mM sodium nitroprusside (SNP) or 0.5 mM N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) for 8 h, was abolished by 24-h pretreatment with either 100 microM SNP, 10 microM spermine NONOate, or 100 microM 8-bromo-cGMP (8-Br-cGMP). Repair of BAECs following wounding, measured as the recovery rate of transendothelial electrical resistance, was delayed by 8-h exposure to 4 mM SNP, and this delay was significantly attenuated by 24-h pretreatment with 100 microM SNP. NO preconditioning produced increased association and expression of soluble guanyl cyclase (sGC) and heat shock protein 90 (HSP90). The protective effect of NO preconditioning, but not the injurious effect of 4 mM SNP, was abolished by either a sGC activity inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) or a HSP90 binding inhibitor (radicicol) and was mimicked by 8-Br-cGMP. We conclude that preconditioning with a low dose of NO donor accelerates repair and maintains endothelial integrity via a mechanism that includes the HSP90/sGC pathway. HSP90/sGC may thus play a role in the protective effects of NO-generating drugs from injurious stimuli.
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PMID:Nitric oxide preconditioning regulates endothelial monolayer integrity via the heat shock protein 90-soluble guanylate cyclase pathway. 1701 59

T lymphocyte activation is associated with nitric oxide (NO) production, which plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both activation and apoptosis of Tlymphocytes, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus induces mitochondrial biogenesis and alters Ca(2+) signaling. Thus, whereas NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity.
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PMID:Nitric oxide, mitochondrial hyperpolarization, and T cell activation. 1746 31

Whilst many physiological functions of nitric oxide (NO) have been revealed so far, recent evidence proposes an essential role for NO in T lymphocyte activation and signal transduction. NO acts as a second messenger, activating soluble guanyl cyclase and participating in signal transduction pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial biogenesis in many cell types, including lymphocytes. Several studies undertaken on patients with RA and SLE have documented increased endogenous NO synthesis, although the effects of NO may be distinct. Here, we discuss recent evidence that NO contributes to T cell dysfunction in both SLE and RA by altering multiple signaling pathways in T cells. Although NO may play a physiological role in lymphocyte cell signaling, its overproduction may perturb T cell activation, differentiation and effector responses, each of which may contribute in different ways to the pathogenesis of autoimmunity.
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PMID:Nitric oxide, chronic inflammation and autoimmunity. 1756 90

The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here, we show that increasing cGMP levels to inhibit epithelial Na(+) channel in cystic fibrosis (CF) respiratory epithelial cells corrects several aspects of the downstream pathology in CF. Cell culture models, using a range of CF cell lines and primary cells, showed that complementary pharmacological approaches to increasing intracellular cGMP, by elevating guanyl cyclase activity though reduced nitric oxide, addition of cell-permeable cGMP analogs, or inhibition of phosphodiesterase 5 corrected multiple aspects of the CF pathological cascade. These included correction of defective protein glycosylation, bacterial adherence, and proinflammatory responses. Furthermore, pharmacological inhibition of phosphodiesterase 5 in tissues ex vivo or in animal models improved transepithelial currents across nasal mucosae from transgenic F508del Cftr(tm1Eur) mice and reduced neutrophil infiltration on bacterial aerosol challenge in Pseudomonas aeruginosa-susceptible DBA/2 mice. Our findings define phosphodiesterase 5 as a specific target for correcting a number of previously disconnected defects in the CF respiratory tract, now linked through this study. Our study suggests that phosphodiesterase 5 inhibition provides an opportunity for simultaneous and concerted correction of seemingly disparate complications in CF.
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PMID:Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. 1758 95

Nitric oxide ((.-)NO) is an important physiological signaling molecule and potent vasodilator. Recently, we have shown abnormal (.-)NO metabolism in the plasma of patients with systemic sclerosis (SSc), a disease that features excessive collagen overproduction as well as vascular dysfunction. The current study investigates the effects of (.-)NO and peroxynitrite (ONOO(-)) on secretion of type I collagen by SSc dermal fibroblasts, compared with those from normal dermal fibroblasts (CON) and a dermal fibroblast cell line (AG). Dermal fibroblasts were incubated with (.-)NO donors (SNP, DETA-NONOate) with or without the antioxidant ascorbic acid, or ONOO(-) for 24-72 h. In CON and AG fibroblasts, type I collagen was dose dependently decreased by SNP or DETA-NONOate. However, (.-)NO had no effect in SSc fibroblasts. Furthermore, the inhibition of collagen synthesis by (.-)NO was reversed by ascorbic acid and was not affected by 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanyl cyclase, or 8-bromoguanosine cyclic 3',5'-monophosphate, a cGMP agonist. SNP also showed a significant up-regulation of matrix metalloproteinase-1 (MMP-1) protein and activity levels, an essential collagenase involved in collagen degradation, in the AG fibroblasts. Additionally, (.-)NO-treated fibroblasts had lower prolyl hydroxylase activity, an enzyme important in the post-translational processing of collagen, while there was no effect on total protein levels. There were no significant effects on type I collagen levels when dermal fibroblasts were treated with ONOO(-). Taken together, ()NO inhibits collagen secretion in normal dermal fibroblasts but regulation is lost in SSc fibroblasts, while ONOO(-) itself is ineffective. (.-)NO inhibition of collagen was by cGMP-independent regulatory mechanisms and in part may be due to up-regulation of MMP-1 and/or inhibition of prolyl hydroxylase. These differences may contribute to the observed pathology of SSc.
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PMID:Effect of nitric oxide and peroxynitrite on type I collagen synthesis in normal and scleroderma dermal fibroblasts. 1760 34

Basic research on estrogen-related changes in cardiomyocyte gene expression is needed to provide a greater understanding of the effects of estrogen, so that hormone replacement trials and treatment can be based on a true comprehension of estrogen's pleiotropic effects. Therefore, we compared gene expression in models of estrogen depletion and estrogen replacement. Using gene expression array analysis, we examined differences in expression in cardiac tissue from ovariectomized (OVX), ovariectomized with 17beta-estradiol replacement (OVX/E2), and intact rats undergoing sham procedures (Sham). We found that OVX results in at least twofold changes in expression of genes involved in inflammation, vascular tone, apoptosis, and proteolysis compared with OVX/E2. With confirmation via real-time PCR, we found an OVX-induced increase in genes mediating inflammation (inhibin betaa, IL-6, TNF-alpha, SOCS2, SOCS3), an OVX-related decrease in the myocardial mRNA expression of genes involved in regulating vasodilation (endothelial NOS, soluble guanyl cyclase), an OVX-associated increase in extracellular matrix genes (collagen12alpha1, connexin 43), and an OVX-related increase in proapoptotic genes (caspase 3, calpain). Because details of cardiac signaling by SOCS genes are virtually unknown, we examined the protein expression for these genes via Western analyses. Although we observed OVX-related increases in SOCS2 and SOCS3 mRNA, SOCS2 and SOCS3 protein did not differ among groups. In light of these findings, investigation into the net effect of OVX on inflammation is warranted. These experiments add to existing evidence that estrogen can protect against negative changes associated with estrogen removal.
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PMID:Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS gene expression. 1798 23

Within the striatum, the gaseous neurotransmitter nitric oxide (NO) is produced by a subclass of interneurons containing the neuronal NO synthase (nNOS). NO promotes the second messenger cGMP through the activation of the soluble guanyl cyclase (sGC) and plays a crucial role in the integration of glutamate (GLU) and DA transmission. The aim of this study was to characterize the impact of 6-hydroxyDA (6-OHDA) lesion of the rat nigrostriatal pathway on NO/cGMP system. In vivo extracellular single units recordings were performed under urethane anesthesia to avoid any potentially misleading contributions of cortically-driven changes on endogenous NO. Hence, no electrical extrastriatal stimulation was performed and great attention was paid to the effects of 3-morpholinosydnonimine (SIN-1, a NO donor), N(G)-nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor) and Zaprinast (a PDE inhibitor) delivered by iontophoresis upon the main striatal phenotypes. The latter were operationally distinguished in silent medium spiny-like neurons (MSN), with negligible spontaneous activity but displaying glutamate-induced firing discharge at rest and spontaneously active neurons (SAN), representing to a large extent nonprojecting interneurons. SANs were excited by SIN-1 and Zaprinast while MSNs showed a clear inhibition during local iontophoretic application of SIN-1 and Zaprinast. In 6-OHDA animals, SIN-1-induced excitation in SANs was significantly increased (on the contrary, the inhibitory effect of L-NAME was less effective). Interestingly, in DA-denervated animals, a subclass of MSNs (40%) displayed a peculiar excitatory response to SIN-1. These findings support the notion of an inhibitory modulatory role exerted by endogenous NO on control striatal projection cells. In addition, these findings suggest a functional cross-talk between NO, spontaneously active interneurons, and projection neurons that becomes critical in the parkinsonian state.
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PMID:In vivo electrophysiology of dopamine-denervated striatum: focus on the nitric oxide/cGMP signaling pathway. 1836 39


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