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)

Previous results have shown that the G alpha protein subunit G alpha 2 is required for aggregation in Dictyostelium discoideum and is essential for coupling cell-surface cAMP receptors to downstream effectors in vivo during this stage of development. G alpha 2 expresses at least four distinct transcripts that are differentially regulated during development; two of the transcripts are expressed exclusively in the multicellular stages and their expression is restricted to prestalk cells. We partially dissected the G alpha 2 promoter and identified a component that is expressed exclusively during the multicellular stages using luciferase gene fusions. When this promoter region is coupled to lacZ, beta-gal expression is restricted to the multicellular stages and localized in prestalk cells with a pattern similar to that of the ecmA prestalk-specific promoter. We show that expression in wild-type cells of the G alpha 2 mutant protein [G alpha 2(G206T)] during the early stages of development blocks aggregation and cAMP-mediated activation of adenylyl cyclase and guanylyl cyclase, suggesting it functions as a dominant negatively active G alpha subunit. When this mutant G alpha protein is expressed from the ecmA prestalk-specific promoter, abnormal stalk differentiation during culmination is observed. Expression of the mutant G alpha 2 from the SP60 prespore promoter or wild-type G alpha 2 from either the ecmA or the SP60 promoter results in no detectable phenotype. The results suggest that G alpha 2 plays an essential role during the culmination stage in prestalk cells and may mediate cAMP receptor activation of these processes during multicellular development.
Mol Biol Cell 1994 Jan
PMID:Spatial and temporal expression of the Dictyostelium discoideum G alpha protein subunit G alpha 2: expression of a dominant negative protein inhibits proper prestalk to stalk differentiation. 818 66

The differential distribution of natriuretic peptide receptor subtypes and their distinct properties were assessed in mammalian cellular models which were screened for their ability to produce cGMP upon stimulation by different natriuretic peptides. The ANF-R1A receptor subtype was distinguished by its selective activation by atrial natriuretic factor (ANF) while the ANF-R1C was characterized by preferential stimulation by C-type natriuretic peptide (CNP). AT-620 pituitary cells, bovine adrenal chromaffin cells, and NIH-3T3 fibroblasts mainly express the ANF-R1C receptor subtype. Other cell lines such as PC12, RASM and GH3 express significant but varying amounts of both ANF-R1A and ANF-R1C subtypes. A10 and NIH cells which express high density of ANF-R2 receptor subtype, also demonstrate a higher sensitivity to CNP over ANF suggesting that they express significant amounts of ANF-R1C. Studies of the regulation by ATP of guanylyl cyclase activity indicate that both ANF-R1A and ANF-R1C subtypes are modulated in the same manner. In the presence of Mn2+, ATP inhibits the CNP-stimulated guanylyl cyclase activity while in the presence of Mg2+ adenine nucleotides potentiate the stimulation by CNP. In addition, we show that like the ANF-R1A, the ANF-R1C guanylyl cyclase activity can be regulated by phosphorylation since preincubation with TPA or FKL attenuates the subsequent stimulation by CNP in cultured cells. The results presented demonstrate that specific cell types express distinct natriuretic peptide receptor subtypes and also that the newly characterized ANF-R1C subtype is regulated by ATP and serine/threonine kinases in the same way as the ANF-R1A subtype.
Mol Cell Biochem 1993 Jul 07
PMID:Distribution and regulation of natriuretic factor-R1C receptor subtypes in mammalian cell lines. 823 74

Nitric oxide (NO) is an intercellular mediator produced within the cerebellum and other central nervous system sites. Results from the present study suggest a novel role for this gaseous second messenger in mediating the stimulatory actions of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) on turnover of phosphatidylinositol (PI) in the neonatal cerebellum. Activation of the NMDA receptor stimulates PI turnover in developing cerebellum when these neurons are in a depolarized state, but the mechanism underlying this effect is unknown. We measured changes in PI hydrolysis induced by NMDA in the presence of baclofen, which is known to depolarize neurons by activating presynaptic inhibitory gamma-aminobutyric acidB autoreceptors. NMDA increased PI hydrolysis by 80% in the presence of 1 microM baclofen. This modulatory action of NMDA was prevented by two competitive inhibitors of NO synthase, L-NG-monomethylarginine and L-N omega-nitroarginine, as well as by hemoglobin, which binds NO. Inhibition of NMDA-induced PI hydrolysis by L-NG-monomethylarginine was reversed by prior administration of L-arginine (200 microM), the physiological substrate of NO synthase. Arginine (500 microM) alone was also able to increase PI hydrolysis significantly. Superoxide dismutase, which prolongs the half-life of NO, also significantly increased the ability of NMDA to stimulate PI hydrolysis. However, NO-induced activation of the cGMP pathway did not appear to be responsible for the NMDA-induced increase in PI hydrolysis, because addition of 8-bromo-cGMP decreased this parameter, and methylene blue, which blocks guanylate cyclase activity, did not inhibit the PI hydrolysis evoked by NMDA receptor activation. These results suggest that NMDA receptor activation acts to release NO, which then acts through a novel pathway to enhance the hydrolysis of PI in the developing rat cerebellum. This novel role for NO in mediating the stimulatory actions of NMDA on PI hydrolysis may be important for developmental processes in the central nervous system.
Mol Pharmacol 1993 Jan
PMID:Novel action of nitric oxide as mediator of N-methyl-D-aspartate-induced phosphatidylinositol hydrolysis in neonatal rat cerebellum. 838 Aug 82

The effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] on ionic current responses produced by ionotropic glutamate and gamma-aminobutyric acid (GABA)A receptor activation in the nucleus of the tractus solitarius (NTS) were examined. Recordings were made in the dorsomedial subdivision of the NTS adjacent to the area postrema in transverse brainstem slices of the rat. (1S,3R)-ACPD produced a small inward current (IACPD) associated with a decrease in conductance in approximately 50% of recordings. Monosynaptic excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation in the region of the tractus solitarius in the presence of D-amino-5-phosphonopentanoic acid and bicuculline were reversibly reduced by (1S,3R)-ACPD in > 90% of cells. The inward current evoked by pressure application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (IAMPA) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the GABAA receptor agonist muscimol (IMUSC) was inhibited. We have previously demonstrated that these effects may involve the activation of soluble guanylate cyclase. The diffusible second messengers nitric oxide and carbon monoxide are known to activate soluble guanylate cyclase. The nitric oxide synthase inhibitor L-omega-nitroarginine failed to inhibit responses to (1S,3R)-ACPD. The selective heme oxygenase inhibitor Zn-protoporphyrin-IX, which would be expected to block the production of carbon monoxide, antagonized the effects of (1S,3R)-ACPD on EPSCs, IAMPA, and IMUSC. However, IACPD was not blocked. A relatively inactive metalloprotoporphyrin, Cu-protoporphyrin-IX was ineffective. A cell-permeant form of cGMP, 8-Br-cGMP inhibited EPSCs, IAMPA, and IMUSC in the presence of Zn-protoporphyrin-IX but did not induce an inward current. These results further support the hypothesis that multiple metabotropic glutamate receptors exist in the NTS, and they suggest that one of these may be coupled to the activation of a soluble guanylate cyclase via the liberation of an easily diffusible second messenger such as carbon monoxide.
Mol Pharmacol 1993 Jun
PMID:Zinc protoporphyrin-IX blocks the effects of metabotropic glutamate receptor activation in the rat nucleus tractus solitarii. 839 Nov 21

A pharmacological characterization of subtypes of the atrial natriuretic factor (ANF) receptor ANF-R1, found in bovine adrenal cortex and rat papillary membrane preparations, has been carried out using various chimeric analogs based on rat ANF(99-126) [rANF(99-126)] and porcine brain natriuretic peptide 32 (pBNP32). Receptor binding and cGMP production assays in bovine adrenal cortex indicate that replacement of the amino-terminal segment of pBNP32 with that of rANF(99-126) enhances the affinity of the peptide for the ANF-R1A receptor subtype and its stimulation of associated guanylate cyclase activity. In rat kidney papillae, the substitution of amino- and/or carboxyl-terminal portions of pBNP32 with those of rANF(99-126) also results in a large increase in the affinity and agonistic potency for the ANF-R1A subtype but in only modest changes in those for the ANF-R1B receptor subtype. Interestingly, in this preparation the chimeric analogs could discriminate by their differential affinities and cGMP production potencies between the two receptor subtypes. In particular, pBNP1, obtained by combining the ring structure of pBNP32 with the amino- and carboxyl-terminal portions of rANF(99-126), is the most selective analog. pBNP1 displays higher affinity and agonistic potency for ANF-R1A receptor than for ANF-R1B receptor, with selectivity ratios between these two subtypes of 632- and 504-fold, respectively. Moreover, an excellent correlation is observed between the affinity of the peptides for the ANF-R1A receptor and their stimulation of particulate guanylate cyclase activity in bovine adrenal cortex (r = 0.99, p < 0.01) and rat papillary (r = 0.97, p < 0.01) membrane preparations. In addition, all the chimeric analogs in this study show affinities similar to those of rANF(99-126) and pBNP32 for the ANF-R2 receptor in NIH-3T3 membrane preparations. Importantly, the chimeric analogs pBNP1 and pBNP3, which contain the core of pBNP32 and the amino-terminal segment of rANF(99-126), display higher affinities for the ANF-R1A receptor type than for the ANF-R2 receptor type. These results indicate that the analogs combining the ring structure of pBNP32 with the amino- and/or carboxyl-terminal segments of rANF(99-126) are more selective for the ANF-R1A receptor subtype than are the natural peptides rANF(99-126) and pBNP32.
Mol Pharmacol 1993 May
PMID:Development of natriuretic peptide analogs selective for the atrial natriuretic factor-R1A receptor subtype. 850 32

Effects of aminoethylisothiuronium bromide (AET), known as radioprotector, on human platelet soluble guanylate cyclase and on ADP-induced human platelets aggregation were studied. It was shown that AET - in Tris buffer and at certain pH values - is converted, via transguanidine rearrangement, to mercaptoethylguanidine. The latter contains in its molecule both the guanidine and SH groups which act as donor and acceptor of nitric oxide (NO), respectively. It was demonstrated that AET, after its rearrangement to mercaptoethylguanidine, is able to activate human platelet soluble guanylate cyclase, as well as to inhibit ADP-induced human stimulatory effect of AET is dependent on the effectiveness of its transguanidine rearrangement to mercaptoethylguanidine. The molecular mechanism of the hypotensive by - effect of AET is proposed.
Biochem Mol Biol Int 1995 Jul
PMID:Guanidine thiol--a new activator of soluble guanylate cyclase with antihypertensive and antiaggregatory properties. 852 55

The broad objective of these studies was to understand the nature of cyclic GMP system and the mechanism(s) whereby hormone, autacoids and drugs alter this signal in various physiological systems. Studies were undertaken on the modulation of guanylate cyclase activity by oxygen-radicals/nitric oxide and the mechanism(s) of generation of nitric oxide by receptor-selective hormones. We observed that cytosolic guanylate cyclase undergoes significant stimulation in the presence of oxygen-radicals/nitric oxide. This activation by nitric oxide can be reversed by hemeproteins, thus, enabling guanylate cyclase system to cycle between activated and deactivated state. The evidence is presented that oxygen-radicals are required for the synthesis of nitric oxide by NO synthase as demonstrated by inhibition of NO formation by oxygen-radical scavengers. And finally, the data is presented that acetylcholine-induced elevations of intracellular levels of cyclic GMP can be attenuated by muscarinic antagonist, atropine and superoxide anion scavenger, nitroblue tetrazolium. These observations establish a novel concept that activation of hormone receptors on the cell surface, triggers generation of oxygen radicals and hydrogen peroxide which participates in the catalytic conversion of L-arginine to nitric oxide by nitric oxide synthase in the presence of calcium ion. The oxygen-radicals/NO, thus formed, oxidatively activate guanylate cyclase and transduce the message of calcium-dependent hormones.
Mol Cell Biochem
PMID:Oxygen-radical/nitric oxide mediate calcium-dependent hormone action on cyclic GMP system: a novel concept in signal transduction mechanisms. 856 37

Recent reports suggest that endothelial-dependent relaxant factor, recognized as nitric oxide (NO), reduces myocardial contractility. Here, we showed that both exposures to acetylcholine and bradykinin for 30 min increased cyclic guanylate monophosphate (cyclic GMP) in isolated rat cardiomyocytes. These increases in cyclic GMP were blunted by NW-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Hypoxia augmented the cyclic GMP accumulation due to exposures to acetylcholine and bradykinin, which were blunted by L-NAME. The increases in cyclic GMP due to acetylcholine and bradykinin during normoxic and hypoxic conditions were not blunted by aminoguanidine, an inhibitor of inducible NO synthase. These findings revealed that NO is produced in cardiomyocytes due to stimulation of NO synthase and modulates their own guanylate cyclase, which was augmented by hypoxia. NO production, through NO synthase in cardiomyocytes, may constitute autocrine regulations of myocardial contractility and paracrine regulations of coronary vasodilation and platelet aggregation.
J Mol Cell Cardiol 1995 Oct
PMID:Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia. 857 31

In vertebrate retina, rod outer segment is the site of visual transduction. The inward cationic current in the dark-adapted outer segment is regulated by cyclic GMP. A light flash on the outer segment activates a cyclic GMP phosphodiesterase resulting in rapid hydrolysis of the cyclic nucleotide which in turn causes a decrease in the dark current. Restoration of the dark current requires inactivation of the phosphodiesterase and synthesis of cyclic GMP. The latter is accomplished by the enzyme guanylate cyclase which catalyzes the formation of cyclic GMP from GTP. Therefore, factors regulating the cyclase activity play a critical role in visual transduction. But regulation of the cyclase by some of these factors--phosphodiesterase, ATP, the soluble proteins and metal cofactors (Mg and Mn)--is controversial. The availability of different types of cyclase preparations, dark-adapted rod outer segments with fully inhibited phosphodiesterase activity, partially purified cyclase without PDE contamination, cloned rod outer segment cyclase free of other rod outer segment proteins, permitted us to address these controversial issues. The results show that ATP inhibits the basal cyclase activity but enhances the stimulation of the enzyme by soluble activator, that cyclase can be activated in the dark at low calcium concentrations under conditions where phosphodiesterase activity is fully suppressed, and that greater activity is observed with manganese as cofactor than magnesium. These results provide a better understanding of the controls on cyclase activity in rod outer segments and suggest how regulation of this cyclase by ATP differs from that of other known membrane guanylate cyclases.
Mol Cell Biochem 1995 Jul 19
PMID:Regulation of bovine rod outer segment membrane guanylate cyclase by ATP, phosphodiesterase and metal ions. 859 18

Both sodium nitroprusside (SNP), a nitric oxide (NO) generator, and C-type natriuretic peptide (CNP) have been found to raise cGMP levels in bovine chromaffin cells in a time- and concentration-dependent manner. The effect of these compounds on catecholamine secretion and calcium influx has also been studied, and both compounds were found to produce a slowly developing inhibitory effect on acetylcholine- or depolarization-stimulated catecholamine secretion and calcium increases without affecting the spontaneous release or the basal intracellular Ca2+ concentration. These inhibitory effects were observed only at high doses of acetylcholine or high levels of extracellular potassium and required concentrations of SNP or CNP very similar to those that increased cGMP levels. Preincubation with 100 microM zaprinast, a cGMP-phosphodiesterase inhibitor able to increase cGMP levels, mimicked the inhibitory effects of SNP and CNP. We investigated the effect of the soluble guanylate cyclase inhibitor methylene blue and the cGMP-dependent protein kinase (PKG) inhibitor 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate, Rp isomer, on inhibition by SNP or CNP. Although methylene blue (10 microM) partially prevented the inhibitory effect of SNP, it did not do so for that produced by CNP, thus indicating that SNP acts through cGMP produced by the NO-activated guanylate cyclase. 8-(4-Chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate, Rp isomer totally reversed both the SNP and CNP inhibitory effects. These results suggest that the activation of PKG mediates the inhibition induced by SNP and CNP. We successfully measured the PKG activity from cells preincubated with SNP or CNP, and our results show that this enzymatic activity increased with a time dependence very similar to the increase in the cGMP levels. Our results indicate that NO and CNP peptide inhibit secretagogue-stimulated catecholamine release via activation of soluble and particulate isoforms of the guanylate cyclase, respectively, presumably by inhibition of calcium entry through voltage-activated calcium channels. This inhibitory effects seems to be mediated by activation of the PKG.
Mol Pharmacol 1996 Jun
PMID:Effect of cyclic GMP-increasing agents nitric oxide and C-type natriuretic peptide on bovine chromaffin cell function: inhibitory role mediated by cyclic GMP-dependent protein kinase. 864 44


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