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)

On the basis of the information presented in this review, it is difficult to reach any firm decision regarding the role of cyclic AMP (or cyclic GMP) in synaptic transmission in the brain. While it is clear that cyclic nucleotide levels can be altered by the exposure of neural tissues to various neurotransmitters, it would be premature to claim that these nucleotides are, or are not, essential to the transmission process in the pre-or post-synaptic components of the synapse. In future experiments with cyclic AMP it will be necessary to consider more critically whether the extracellularly applied nucleotide merely provides a source of adenosine and is thus activating an extracellularly located adenosine receptor, or whether it is actually reaching the hypothetical sites at which it might act as a second messenger. The application of cyclic AMP by intrcellular injection techniques should minimize this particular problem, although possibly at the expense of new diffulties. Prio blockade of the adenosine receptor with agents such as theophylline or adenine xylofuranoside may also assist in the categorization of responses to extracellularly applied cyclic AMP as being a result either of activation of the adenosine receptor or of some other mechanism. Utimately, the developement of highly specific inhibitor for adenylate cyclase should provide a firm basis from which to draw conclusions about the role of cyclic AMP in synaptic transmission. Similar considerations apply to the action of cyclic GMP and the role of its synthesizing enzyme, guanylate cyclase. The use of phosphodiesterase inhibitors in studies on cyclic nucleotides must also be approached with caution. The diverse actions of many of these compounds, which include calcium mobilization and block of adenosine uptake, could account for many of the results that have been reported in the literature.
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PMID:The role of cyclic nucleotides in the CNS. 1 46

The response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary arterial hypoxic contraction: signal transduction. 135 5

We investigated the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in adenosine (ADO) receptor-mediated coronary artery relaxation. Rings from left anterior descending coronary artery, with the endothelium mechanically removed, contracted with prostaglandin F2 alpha and relaxed in a concentration-dependent manner to ADO, 2-chloroadenosine (CAD), l-N6-(2-phenylisopropyl)adenosine (R-PIA), and 5'-(N-ethylcarboxamido)adenosine (NECA). These relaxations were blocked by addition of the ADO receptor antagonist 8-(sulfophenyl)theophylline (8-SPT), indicating ADO receptor involvement. In an endothelium-free membrane preparation, ADO, CAD, and R-PIA all stimulated adenylate cyclase activity in a concentration-dependent manner, and these responses were blocked by 8-SPT. The increase in adenylate cyclase activity produced by ADO, CAD, and R-PIA was completely dependent on the presence of guanosine 5'-triphosphate, suggesting G protein involvement. Surprisingly, NECA and CGS-21680 did not increase adenylate cyclase activity. Unlike atrial natriuretic factor, neither NECA, CAD, R-PIA, nor ADO increased guanylate cyclase activity, suggesting that cGMP is not involved in ADO receptor-mediated relaxation. Data presented in this study support the hypothesis that ADO receptor-mediated coronary artery relaxation may involve cAMP; however, the inability of NECA and CGS-21680 to stimulate adenylate cyclase suggests that the ADO receptor-signaling mechanisms in coronary artery may be more complicated than agonist interaction with a single adenylate cyclase-coupled A2 adenosine receptor.
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PMID:Adenosine receptor-mediated coronary artery relaxation and cyclic nucleotide production. 167 30

We have investigated the effect of NZ-107, an inhibitor of bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A), on tracheal responses to adenosine in the guinea pig. In the presence of an adenosine uptake inhibitor, dipyridamole (1 microM), NZ-107 (0.3-1 microM) enhanced adenosine-induced relaxation in 30 nM leukotriene D4 (LTD4)-precontracted trachea, whereas aminophylline (AP, 10-30 microM), an adenosine receptor antagonist, markedly inhibited it. NZ-107 (1 microM) also enhanced the relaxation induced by forskolin, an adenylate cyclase activator, but not that by nitroprusside (NP), a guanylate cyclase activator. AP (30 microM) affected neither forskolin- nor NP-induced relaxation. NZ-107 (1 microM) and AP (30 microM) inhibited to about the same extent the contractile response to an adenosine A1 receptor agonist, the R(-)-enantiomer of N6-(2-phenylisopropyl)-adenosine (R-PIA). The R-PIA-induced contraction was completely blocked by 5 microM indomethacin. NZ-107 (1 microM) did not affect the contraction induced by PGD2, but significantly reduced that of PGF2 alpha. AP (30 microM) had no effect on PGF2 alpha- and PGD2-induced contractions. These results suggest that NZ-107 may have a unique profile for adenosine responses in bronchial asthma.
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PMID:Effects of NZ-107 on tracheal responses to adenosine in the guinea pig. 188 Sep 89

1. Depolarization of excitable cells of the central nervous system results in the formation of the second messengers cyclic AMP, cyclic GMP, inositol phosphates, and diacylglycerides. 2. Depolarization-evoked accumulation of cyclic AMP in brain preparations can be accounted for mainly by the release of adenosine, which subsequently interacts with stimulatory adenosine receptor linked to adenylate cyclase. 3. Depolarization-evoked formation of cyclic GMP in brain preparations is linked to activation of voltage-dependent calcium channels, presumably leading to activation of guanylate cyclase by calcium ions. 4. In brain slices depolarization-evoked stimulation of phosphoinositide breakdown and subsequent formation of inositol phosphates and diacylglycerides are linked to activation of voltage-dependent calcium channels, which are sensitive to dihydropyridines, presumably leading to activation of phospholipase(s) C by calcium ions. 5. In the synaptoneurosome preparation depolarization-evoked stimulation of phosphoinositide breakdown does not involve activation of dihydropyridine-sensitive calcium channels and, instead, appears to be regulated primarily by the intracellular concentration of sodium ions. Thus, agents that induce increases in intracellular sodium--such as toxins that open or delay inactivation of voltage-dependent sodium channels; ouabain, an inhibitor of Na+/K+ ATPase that transports sodium outward and a sodium ionophore--all stimulate phosphoinositide breakdown. Mechanistically, increases in intracellular sodium either might directly affect phospholipase(s) C or might lead to influx of calcium ions through Na+/Ca2+ transporters. 6. Depolarization-evoked stimulation of cyclic AMP formation and phosphoinositide breakdown can exhibit potentiative interactions with responses to receptor agonists, thereby providing mechanisms for modulation of receptor responses by neuronal activity. 7. Since all these second messengers can induce phosphorylation of ion channels through the activation of specific kinases, it is proposed that depolarization-evoked formation of second messengers represents a putative feedback mechanism to regulate ion fluxes in excitable cells.
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PMID:Formation of second messengers in response to activation of ion channels in excitable cells. 245 43

Adenosine produces tone-dependent pulmonary vascular responses; however, the adenosine receptor subtype mediating these responses is unknown. In the present study, the adenosine receptor subtypes mediating tone-dependent responses were investigated, Intralobar injections of adenosine,ATP, and analogues under low-tone conditions caused dose-related increases in lobar arterial pressure; the order of potency was alpha,beta-methylene ATP (alpha,beta-metATP) > N6-cyclopentyladenosine (CPA) > ATP > adenosine. Under low-tone conditions, pressor responses to adenosine, ATP, and CPA, an adenosine A1-receptor agonist, were reduced by KW-3902, an adenosine A1-receptor antagonist, whereas KW-3902 and meclofenamate had no effect on responses to alpha,beta-metATP, norepinephrine, serotonin, or angiotensin II. Under elevated-tone conditions, injections of adenosine, ATP, and analogues caused dose-related decreases in lobar arterial pressure, and adenosine was 10-fold less potent than 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), an A2-receptor agonist, and ATP. KF-17837, an A2-receptor antagonist, reduced vasodilator responses to adenosine and CPCA, whereas responses to ATP, isoproterenol, diethylamine-NO, lemakalim, and bradykinin were not changed. The vasodilator responses to adenosine were not attenuated by Nw-nitro-L-arginine benzyl ester, methylene blue, or U-37883A. These results suggest that vasoconstrictor responses to adenosine are mediated by A1 receptors and the release of vasoconstrictor prostanoids, and that, under elevated-tone conditions, vasodilator responses are mediated by A2 receptors but not the release of nitric oxide or the activation of guanylate cyclase or K+ATP channels.
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PMID:Adenosine A1 and A2 receptors mediate tone-dependent responses in feline pulmonary vascular bed. 876 52

The role of the intracellular second messengers guanosine 3', 5'-cyclic monophosphate (cGMP) and adenosine 3', 5'-cyclic monophosphate (cAMP) in the control of macromolecule permeability was studied in cultured monolayers of microvascular coronary endothelial cells from rat. Macromolecule permeability was determined as passage of fluorescein isothiocyanate (FITC)-labeled albumin across the monolayers. Activation of adenylyl cyclase by the beta-adrenoceptor agonist isoproterenol (Iso; 10(-5) M) and the A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-7) M) induced an increase in cellular cAMP contents that was accompanied by an increase in albumin flux. Effects of Iso and NECA on cellular cAMP level and albumin flux could be antagonized by a stimulator of the particular guanylyl cyclase, atrial natriuretic peptide (ANP; 10(-7) M), and stimulators of the soluble guanylyl cyclase, 3-morpholinosydnonimine (SIN-1; 10(-7) M) and sodium nitroprusside (SNP; 10(-6) M). ANP, SIN-1, and SNP also reduced cAMP content and basal macromolecule flux in unstimulated monolayers. 8-Bromoguanosine 3', 5'-cyclic monophosphate (8-BrcGMP; 5 x 10(-6) M), a stimulator of protein kinase G, reduced the increase in albumin flux under Iso (10(-5) M), NECA (10(-7) M), or 8-bromoadenosine 3', 5'-cyclic monophosphate (8-BrcAMP; 5 x 10(-6) M). The present study shows that cGMP and cAMP are functional antagonists in the control of macro molecule permeability.
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PMID:Functional antagonism between cAMP and cGMP on permeability of coronary endothelial monolayers. 896 65

The effect and mechanism of action of adenosine on the pulmonary circulation of rabbits were studied. Adenosine (10(-5)-10(-3) M) produced a concentration-dependent decrease in pulmonary arterial tension of precontracted pulmonary arterial rings. Removal of endothelium (denuded) augmented the adenosine-induced vasodilation in the pulmonary arterial rings. Theophylline (5 x 10(-5) M), an adenosine receptor antagonist, reduces the vasodilation induced by adenosine in intact and denuded rings. Pretreatment of the pulmonary rings with the cyclooxygenase inhibitor indomethacin (5 x 10(-6) M) significantly attenuated the adenosine-induced relaxation in denuded but not in the intact pulmonary arterial rings. Methylene blue (5 x 10(-5) M), a guanylate cyclase inhibitor, significantly reduced the relaxation induced by adenosine in both the intact and the denuded arterial rings. Adenosine significantly attenuated the pressor responses of serotonin and acetylcholine in the intact and denuded rabbit's pulmonary arterial rings. The results of this study indicate that adenosine induces pulmonary vasodilation and that functional endothelium is not required to evoke this dilation. In addition, guanylate cyclase activity and the generation of cGMP is essential for adenosine to induce vasodilation in the rabbit lung. Furthermore, the results of this study may suggest that adenosine could be used to reduce the severity of pulmonary hypertension and possibly pulmonary edema.
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PMID:Effect of adenosine on pulmonary circulation of rabbits. 1021 84

Serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) are critical determinants of synaptic 5-HT inactivation and the targets for multiple drugs used to treat psychiatric disorders. In support of prior studies, we found that short-term (5-30 min) application of the adenosine receptor (AR) agonist 5'-N-ethylcarboxamidoadenosine (NECA) induces an increase in 5-HT uptake Vmax in rat basophilic leukemia 2H3 cells that is enhanced by pretreatment with the cGMP phosphodiesterase inhibitor sildenafil. NECA stimulation is blocked by the A3 AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(+/-)dihydropyridine-3,5-dicarboxylate (MRS1191), by the phospholipase C inhibitor 1-(6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl)-1H-pyrrole-2,5-dione (U73122), by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, and by the guanyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Hydroxylamine, a nitric-oxide donor, and 8-bromo-cGMP, a membrane-permeant analog of cGMP, mimic the effects of NECA on 5-HT uptake, whereas the protein kinase G (PKG) inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) blocks NECA, hydroxylamine, and 8-bromo-cGMP effects. NECA stimulation activates p38 mitogen-activated protein kinase (MAPK), whereas p38 MAPK inhibitors block NECA stimulation of SERT activity, as does the protein phosphatase 2A (PP2A) inhibitor calyculin A. 5-HT-displaceable [125I]3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid methylester tartrate (RTI-55) whole-cell binding is increased by NECA or sildenafil, and both surface binding and cell surface SERT protein are elevated after NECA or sildenafil stimulation of AR/SERT-cotransfected Chinese hamster ovary cells. Whereas p38 MAPK inhibition blocks NECA stimulation of 5-HT activity, it fails to blunt stimulation of SERT surface density. Moreover, inactivation of existing surface SERTs fails to eliminate NECA stimulation of SERT. Together, these results reveal two PKG-dependent pathways supporting rapid SERT regulation by A3 ARs, one leading to enhanced SERT surface trafficking, and a separate, p38 MAPK-dependent process augmenting SERT intrinsic activity.
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PMID:Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation. 1515 39

We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, G(i/o)-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca(2+)-channel blocker omega-conotoxin GVIA selectively blocked SIN-1-induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca(2+)-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A(1) adenosine receptors.
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PMID:3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. 1532 40


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