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)

Although the ability of somatostatin (ST) to relax cultured rat mesangial cells has recently been described, the intimate cellular mechanisms responsible for this effect have not been adequately clarified. The present experiments were designed to test the hypothesis that cyclic GMP (cGMP) could be involved in the genesis of this relaxation. ST increased cGMP synthesis by cultured rat mesangial cells, in basal conditions and in the presence of isobutylmethylxanthine or zaprinast. This effect was dose-dependent, with a threshold value of about 1 nM and a maximal response at ST concentrations between 0.1 and 1 microM. This increased cGMP synthesis was dependent on the stimulation by ST of a particulate guanylate cyclase, as the synthesis of cGMP by a particulate membrane fraction obtained from the cells increased in the presence of ST. When the cGMP-specific phosphodiesterase of mesangial cells was blocked with zaprinast, the ST-dependent relaxation, assessed both by morphological and biochemical criteria, significantly increased with respect to the experiments performed without zaprinast. These results support a role for cGMP in the ST-dependent relaxation of cultured rat mesangial cells. The increased cGMP synthesis appears to be the consequence of the activation of some form of particulate guanylate cyclase.
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PMID:Somatostatin activates particulate guanylate cyclase in cultured rat mesangial cells. 770 18

An indazole derivative, YC-1, was identified in this study to be capable of reversibly and effectively inhibiting proliferation of rat A10 vascular smooth-muscle cells (VSMCs) in vitro. YC-1 (1-100 microM) dose-dependently inhibited [3H]thymidine incorporation into DNA in rat A10 VSMCs that were synchronized by serum depletion and then restimulated by addition of 10% foetal calf serum (FCS), whereas FCS-induced [3H]thymidine incorporation into rat synchronized endothelial cells was unaffected by this agent. The dose of YC-1 required to cause inhibition of FCS-induced proliferation was similar to that necessary for the formation of cellular cyclic GMP (cGMP). Guanylate cyclase activity in soluble fractions of VSMCs was activated by YC-1 (1-100 microM), whereas cGMP-specific phosphodiesterase activity was unaffected by this compound. The anti-proliferative effect of YC-1 was mimicked by 8-bromo-cGMP, a membrane-permeable cGMP analogue, and was antagonized by KT 5823 (0.2 microM), a selective inhibitor of protein kinase G. The anti-proliferative effect of YC-1 was also antagonized by Methylene Blue (50 microM), a guanylate cyclase inhibitor, and was potentiated by 3-isobutyl-1-methylxanthine (500 microM), a phosphodiesterase inhibitor. These results verified that YC-1 is a direct soluble guanylate cyclase activator in A10 VSMCs, and the anti-proliferative effect of YC-1 is mediated by cGMP. YC-1 still inhibited FCS-induced DNA synthesis even when added 10-18 h after restimulation of the serum-deprived A10 VSMCs with 10% FCS. Flow cytometry in synchronized populations revealed an acute blockage of FCS-inducible cell-cycle progression at a point in the G1/S-phase in YC-1 (100 microM)-treated cells. The inhibition of proliferation by YC-1 was demonstrated to be independent of cell damage, as documented by several criteria of cell viability. In conclusion, YC-1 reversibly and effectively inhibited the proliferation of VSMCs, suggesting that it has potential as a therapeutic agent in the prevention of vascular diseases.
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PMID:Mechanism of anti-proliferation caused by YC-1, an indazole derivative, in cultured rat A10 vascular smooth-muscle cells. 984 40

3',5'-Cyclic guanosine monophosphate is the intracellular second messenger regulating phototransduction in mammals. The level of cGMP in photoreceptor cells is controlled by the cGMP-hydrolyzing enzyme cGMP phosphodiesterase and the cGMP-producing enzyme guanylate cyclase. Identification of a photoreceptor-specific guanylate cyclase (retGC) that may function in visual transduction was recently reported. As an initial step in assessing the potential for defects in the retGC (GUC2D) gene to be causal of hereditary retinal disease, we have determined its chromosome location. A 720-bp region of the human GUC2D locus was amplified with exon-specific primers. The amplified product contains three introns, two intact exons, and part of two additional exons, suggesting a high degree of structural complexity. PCR analysis of human-rodent somatic cell hybrids was used to map the GUC2D locus to chromosome 17. This assignment was confirmed and a more precise localization to 17p13.1 was obtained by fluorescence in situ hybridization.
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PMID:Human retinal guanylate cyclase (GUC2D) maps to chromosome 17p13.1. 780 40

The effect of light adaptation on the period of photocurrent saturation induced by a bright stimulating flash was examined in rod photoreceptors of the larval-stage tiger salamander (Ambystoma tigrinum). Using suction electrodes, photocurrent responses to brief flashes were recorded from single, isolated rods in the presence and absence of steady background illumination. Background light decreased the saturation period (T) measured at fixed flash intensity (fixed If) and in this respect light-adapted the saturating response. Effects of the background on responses to weak (i.e. subsaturating) and bright flashes were compared with changes in a parameter, phi = e-delta T/TR*, where delta T is the decrease in saturation period, and where TR* is the slope of the line that relates T and ln If in a given state of adaptation. Dark- and light-adapted responses to flash intensities IDf and ILf, respectively, exhibited similar absolute peak photocurrent and falling-phase kinetics when IDf and ILf satisfied the relation, IDf = phi (ILf + IbTR*), where Ib is the background intensity. It is argued that phi approximates the relative PDE*/R* gain of transduction, i.e. the relative peak level of activated cGMP phosphodiesterase (PDE*) produced by a given, small amount of photoactivated visual pigment (R*). Interpreted on this view, the results imply that light adaptation derives largely from a decrease in PDE*/R gain, rather than from the stimulation of guanylate cyclase activity. The data are consistent with the possibility that modulation of the lifetime of PDE* underlies the background dependence of phi.
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PMID:Modulation of transduction gain in light adaptation of retinal rods. 801 83

Adrenergic stimulation of the adult pineal gland increases cAMP and cGMP production by over 100-fold. beta-Adrenergic stimulation results in Gs alpha-mediated cyclase activation; alpha 1-adrenergic activation potentiates the beta-adrenergic effects through mechanisms mediated by the intracellular Ca2+ concentration ([Ca2+]i) and Ca(2+)-phospholipid-dependent protein kinase. Development analysis of these responses has indicated that the adrenergic stimulation of cAMP is present several days after birth, but the cGMP response develops only after the second week of life. In the study presented here, the adrenergic-->cGMP response was analyzed in pineal glands from 10- and 25-day-old rats, with the intention of determining the basis of the developmental appearance of this response. Organ culture and tissue homogenate studies indicated that guanylate cyclase activity, cGMP phosphodiesterase activity, and adrenergic elevation of phospholipase-A2 were similar in pineal glands from 10- and 25-day-old rats. Norepinephrine stimulated an increase in [Ca2+]i in dispersed pinealocytes from 10-day-old rats, as has been previously demonstrated in adult pinealocytes. In contrast, several treatments that elevate [Ca2+]i had no effect on cGMP accumulation in forskolin-treated or beta-adrenergically activated glands from 10-day-old rats, but were fully effective in similarly treated glands from 25-day-old rats. However, glands from 10-day-old animals showed a 33-fold accumulation of cGMP when they were cultured together with glands from 25-day-old rats. These studies indicate that whereas many elements in the system that mediate adrenergic regulation of pineal cGMP are fully developed at 10 days of age, the developmental appearance of the cGMP response is triggered by the development of a process down-stream of the alpha 1-adrenergic stimulation of [Ca2+]i, and this process may involve a diffusible factor.
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PMID:Developmental appearance of pineal adrenergic-->guanosine 3',5'-monophosphate response is determined by a process down-stream from elevation of intracellular Ca2+: possible involvement of a diffusible factor. 809 11

In rat aorta, KT2-734 inhibited contractile responses to 5-hydroxytryptamine (5-HT) and KCl. KT2-734 inhibited the relaxing effect of verapamil, but not nifedipine. Similarly, verapamil, but not nifedipine, inhibited the vasorelaxing effect of KT2-734. KT2-734 relaxation was inhibited by endothelium removal but not by atropine and propranolol. Methylene blue, a guanylyl cyclase inhibitor, and NG-monomethyl arginine also inhibited the relaxation both in the presence and absence of endothelium. In the absence of endothelium, KT2-734 potentiated the relaxation induced by L-arginine, nitroglycerin and isoproterenol. In addition, M & B 22,948, a cGMP phosphodiesterase inhibitor, and theophylline inhibited and potentiated, respectively, KT2-734-induced relaxation. However, methylene blue inhibited the potentiation of isoproterenol relaxation by KT2-734 and that of KT2-734-relaxation by theophylline. KT2-734 caused increases in the level of cGMP without significantly affecting the cAMP level. These results suggest that KT2-734 may cause endothelium-independent relaxation mainly due to inhibition of cGMP-phosphodiesterase.
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PMID:Vasoinhibitory action of KT2-734, an antihypertensive agent, in isolated rat aorta. 813 65

We sought to determine whether the L-arginine-nitric oxide-guanosine 3',5'-cyclic monophosphate (cGMP) pathway, known to mediate neurostimulation-induced smooth muscle relaxation in penile tissue of rabbits and humans in vitro, is operative also in vivo. Adult male dogs (n = 9) were subjected to direct electrical stimulation of the pelvic nerves to induce penile tumescence. Intracavernous injection of the nitric oxide-releasing substance S-nitroso-N-acetylpenicillamine resulted in similar tumescence. Intracavernous injection of a specific inhibitor of nitric oxide synthesis, NG-nitro-L-arginine, blocked pelvic nerve-stimulated tumescence, and this was partially reversed by intracavernous injection of the nitric oxide precursor L-arginine. Furthermore, neurostimulated tumescence was inhibited by methylene blue, an inhibitor of cytosolic guanylate cyclase and enhanced by M&B 22948, a cGMP phosphodiesterase inhibitor. These in vivo findings support the hypothesis that cavernous smooth muscle relaxation and penile tumescence are mediated by nitric oxide and cGMP.
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PMID:Nitric oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs. 838 56

In vertebrate photoreceptors, light induces hydrolysis of cGMP by activating cGMP phosphodiesterase (PDE), which results in closure of the cGMP-activated cation channel. During light adaptation, the cytoplasmic Ca2+ concentration decreases, and this decrease is one of the underlying mechanisms of light adaptation. Sensitivity-modulating protein (S-modulin) is a Ca(2+)-binding protein involved in light adaptation in frog rods; it regulates both the light sensitivity of PDE and the lifetime of activated PDE by controlling rhodopsin phosphorylation in a Ca(2+)-dependent manner. Recoverin has been reported as a Ca(2+)-dependent regulator of guanylate cyclase in bovine rods (Dizhoor, A. M., Ray, S., Kumar, S., Niemi, G., Spencer, M., Brolley, D., Walsh, K. A. Philipov, P. P., Hurley, J. B., and Stryer, L. (1991) Science 251, 915-918). Here, we show that recoverin has similar activity as S-modulin, and the amino acid sequences of both proteins are similar. The results strongly suggest that recoverin is bovine S-modulin and regulates PDE activation.
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PMID:Recoverin has S-modulin activity in frog rods. 839 55

A simple protocol was developed to isolate the integral membrane guanylate cyclase from bleached bovine photoreceptor outer segments. Hypotonic and hypertonic washes strip the photoreceptor outer segment membranes of peripheral proteins. The guanylate cyclase activity is solubilized by dodecyl-b-D-maltoside in a low salt concentration buffer. Phosphatidylcholine, glycerol, and dithiothreitol are used to stabilize the activity during chromatography. GTP-affinity chromatography achieves a 250-fold increase in specific activity over that of membranes stripped of peripheral proteins. From 100 retinas, the protocol yields 100-140 mg of purified guanylate cyclase composed of a 115-kDa subunit. The molar ratio of the guanylate cyclase to rhodopsin is estimated to be 1:440. A significant portion of the freshly solubilized enzyme behaves as a monomer with a Stokes radius of 48.7 A, whereas the purified protein forms homooligomers ranging from dimers to tetramers. These properties are similar to those of ANP and guanylin receptors, indicating that the photoreceptor protein shares characteristics of the membrane receptor guanylate cyclase family. For the physiological substrate MgGTP, the Km and Vmax are 1.07 +/- 0.20 mM and 3262 +/- 514 nmol cGMP min-1 mg-1, respectively, generating a turnover rate of approximately 3.9 nmol cGMP s-1 at physiological substrate concentrations. The relatively high Km suggests that in vivo changes in GTP concentration might modulate the rate of cGMP synthesis. These properties indicate that the photoreceptor membrane guanylate cyclase can sustain a rate of cGMP synthesis comparable to the dark-adapted (basal) rate of cGMP degradation by the cGMP phosphodiesterase.
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PMID:The bovine photoreceptor outer segment guanylate cyclase: purification, kinetic properties, and molecular size. 852 37

We have used cultured PC12 cells and rat sympathetic neurons as model systems to examine the regulation of neuronal cell death and survival. Because nitric oxide (NO) may be involved in nerve growth factor (NGF) signaling in PC12 cells, we tested NO-generating compounds for their ability to protect PC12 cells and sympathetic neurons from death after withdrawal of trophic support. Three such agents, S-nitroso-N-acetylpenicillamine (SNAP), diethylenetriamine NO adduct (DETA-NO), and sodium nitroprusside provide (SNP), were found to promote complete short-term survival after removal of serum from naive PC12 cells and of NGF from neuronally differentiated PC12 cells and sympathetic neurons. One major target of NO action is guanylate cyclase, which is activated by nitrosylation of its heme prosthetic group. We observed that inhibition of guanylate cyclase blocks the protective effects of the NO generators on trophic factor-deprived PC12 cells and sympathetic neurons without preventing NGF-induced survival. We also found that permeant cGMP analogs and an inhibitor of cGMP-specific phosphodiesterase enhance cell survival, suggesting that the protective effects of NO are mediated by activation of guanylate cyclase and increased intracellular cGMP. N-Nitro-L-arginine methyl ester, a NO synthase inhibitor, did not block NGF-promoted PC12 cell or sympathetic neuron survival. These findings indicate that like NGF, NO has survival-promoting actions on neurons but that the two agents work by initially independent mechanisms.
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PMID:Nitric oxide delays the death of trophic factor-deprived PC12 cells and sympathetic neurons by a cGMP-mediated mechanism. 860 12


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