Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Centrifugation of homogenates of bovine retinas to isopycnic equilibrium in sucrose density gradients yielded three partially overlapping bands of particles which were, in the order of increasing density: (a) photoreceptor cell (rod) outer segments; (b) plasma membranes, lysosomes, and large fragments of endoplasmic reticulum; and (c) mitochondria. The only enzyme activity investigated which had a peak coinciding only with outer segment fractions was guanylate cyclase. Enzyme activities with peaks in both the outer segment and denser fractions included 5'-nucleotidase and cyclic GMP phosphodiesterase. Enzyme activities with peaks only in the denser fractions included sodium and potassium ion-activated ATPase ((Na+ + K+)-ATPase), adenylate cyclase, cyclic AMP phosphodiesterase, beta-glucosidase, beta-galactosidase, and succinate-dependent cytochrome c reductase. These results suggest that some of the activities once thought to be present in rod outer segments are actually present in particles from elsewhere in the retina which contaminate rod outer segment preparations.
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PMID:Distribution of enzyme activities in subcellular fractions of bovine retina. 0 65

Aggregation of human washed platelets with collagen is accompanied by a concentration-dependent increase in cyclic GMP but not cyclic AMP. NG-Monomethyl-L-arginine (L-MeArg), a selective inhibitor of nitric oxide (NO) synthesis from L-arginine, reduces this increase and enhances aggregation. L-Arginine, which has no effect on the basal levels of cyclic GMP, augments the increase in this nucleotide induced by collagen and also inhibits aggregation. Both of these effects of L-arginine are attenuated by L-MeArg. The anti-aggregatory action of L-arginine is potentiated by prostacyclin and by M&B22948, a selective inhibitor of the cyclic GMP phosphodiesterase, but not by HL725, a selective inhibitor of the cyclic AMP phosphodiesterase. L-Arginine also inhibits platelet aggregation in whole blood in a similar manner, although the concentrations required are considerably higher. L-Arginine stimulates the soluble guanylate cyclase and increases cyclic GMP in platelet cytosol. This stimulation is dependent on NADPH and Ca2+ and is associated with the formation of NO. Both the formation of NO and the stimulation of the soluble guanylate cyclase induced by L-arginine are enantiomer specific and abolished by L-MeArg. Thus, human platelets contain an NO synthase which is activated when platelets are stimulated. The consequent generation of NO modulates platelet reactivity by increasing cyclic GMP. Changes in the activity of this pathway in platelets may have physiological, pathophysiological, and therapeutic significance.
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PMID:An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. 169 13

Tetrahymena calmodulin (CaM) differs from mammalian CaM in its ability to activate Tetrahymena guanylate cyclase. Of 12 differences in amino acid sequence, two occur near the carboxyl terminus (Gln-143----Arg and Thr-146----deletion). To investigate the functional significance of the carboxyl-terminal region in activation of the guanylate cyclase, three mutated CaMs were engineered by using cassette mutagenesis of rat CaM cDNA: Gln-143----Arg (CaM.A), Thr-146----deletion (CaM.D), and Gln-143----Arg/Thr-146 deletion (CaM.AD). Recombinant wild type CaM (wCaM), CaM.A, CaM.D, and CaM.AD were indistinguishable in their ability to activate cyclic AMP phosphodiesterase. The two mutated CaMs (CaM.A and CaM.AD) with the Gln-143 replacement activated guanylate cyclase of Tetrahymena plasma membrane in the presence of Ca2+, with the maximal activation being half of that produced by Tetrahymena CaM. In contrast, neither CaM.D nor wCaM could stimulate the cyclase activity. A CaM antagonist, W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide), prevented the cyclase activation by either Tetrahymena CaM, CaM.A, or CaM.AD. Thus, we conclude that Arg-143 is in a region of the molecule involved in activation of Tetrahymena guanylate cyclase. The data also suggest that the cyclase activation by Tetrahymena CaM requires complex macromolecular interactions between the entire CaM molecule and the enzyme.
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PMID:Site-directed mutagenesis of glutamine residue of calmodulin. Activation of guanylate cyclase of Tetrahymena plasma membrane. 196 9

The contractile response to neurally released norepinephrine (NE) from sympathetic nerve endings innervating vascular smooth muscle are inhibited by substances which raise either cyclic AMP and cyclic GMP concentrations in smooth muscle. However, cyclic AMP is believed to facilitate NE release from sympathetic nerves whereas the role of cyclic GMP in this process is undefined. We examined the effects of presumed modulation of the intraneuronal concentration of cyclic AMP and cyclic GMP on sympathetic neurotransmission to isolated canine mesenteric artery by measurement of the efflux of [2-14C]NE during transmural nerve stimulation (calcium dependent release of NE) and administration of tyramine (calcium independent release of NE) and measurement of the contractions to exogenous NE and tyramine. Stimulation of adenylate cyclase with forskolin, prostacyclin and iloprost, a stable prostacyclin analog, and inhibition of Type III cyclic AMP phosphodiesterase with neural specific rolipram, 'non-specific pelrinone and milrinone and isobutylmethylxanthine did not enhance the efflux of [2-14C]NE from sympathetic nerves innervating the blood vessels. Isoproterenol enhanced the efflux of [2-14C]NE. The effect was inhibited by propranolol but not affected by milrinone, amrinone or rolipram. Activators of guanylate cyclase (SIN-1a an active metabolic of molsidomine, nitroglycerin and sodium nitroprusside) and inhibitors of Type II cyclic GMP phosphodiesterase (M&B-22948 and verofyllin) inhibited the efflux of NE released by transmural nerve stimulation but not by tyramine. These data support the conclusion that cyclic GMP may be an inhibitory modulator of calcium and depolarization dependent NE release from sympathetic nerves, whereas neuronal cyclic AMP may not be a primary modulator of neurotransmission to vascular smooth muscle.
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PMID:Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle. 198 54

Adenylate cyclase and cyclic AMP phosphodiesterase activities in the thyroid gland were significantly reduced after hypophysectomy, followed by a gradual restoration of the enzyme activities to the levels seen in sham-operated rats whereas a slight and persistent reduction was evident in guanylate cyclase and cyclic GMP phosphodiesterase activities in the same tissue. These changes in enzyme activities were restored by TSH administration but not by ACTH. The recovery of activity produced by TSH administration was inhibited by cycloheximide. Hypophysectomy, or TSH and cycloheximide administration, did not produce any significant changes in the concentrations of calmodulin, suggesting that the alteration of these enzyme activities is not induced by a decrease in the concentration of calmodulin. Since forskolin activation of adenylate cyclase did not restore the reduced activity in the hypophysectomized rat thyroid to the level found in the sham-operated control rat thyroid, we conclude that there is a reduction of the amount of enzyme after hypophysectomy rather than a change of the active site on adenylate cyclase. The spontaneous restoration of adenylate cyclase and cyclic AMP phosphodiesterase activities after hypophysectomy implies that cyclic AMP-metabolizing enzymes are responsive to an autoregulatory mechanism in thyroid follicular cells.
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PMID:Effect of hypophysectomy on cyclic 3',5'-nucleotidemetabolizing enzymes in the rat thyroid gland. 286 Jan 96

Male ICR mice, immature (25 days old), mature adult (3 months old) and aged (22 months old), were injected with morphine sulfate (10 mg/kg, SC) or were implanted with morphine pellets (75 mg). Age-matched controls received saline injections or placebo pellets. One hour after injections and 72 hours after pellet implantation (when tolerance to morphine had occurred), the mice were decapitated and the frontal cortex and cerebellum were removed. Basal activities of adenylate cyclase, guanylate cyclase, cyclic AMP phosphodiesterase and cyclic GMP phosphodiesterase were determined in both brain regions. Results showed that there are age- and region-differentiated effects of morphine on these enzymes.
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PMID:Age-induced differentiation of morphine's effect on cyclic nucleotide metabolism. 289 Oct 56

Six weeks following complete unilateral surgical isolation of the rat caudate nucleus, activation of adenylate cyclase was reduced in response to dopamine (DA), norepinephrine (NE), 5' -guanylyl-imidodiphosphate [Gpp(NH)p], DA + Gpp(NH)p, and NaF. The low Km form of cyclic AMP phosphodiesterase was elevated in the isolated side when compared to the intact caudate. No changes in activities of guanylate cyclase or in high Km cyclic AMP phosphodiesterase (with or without the calcium-dependent regulator protein, calmodulin or CDR) were observed between the control and isolated caudate. Histologically, the neural damage to the isolated caudate was principally confined to reduced numbers of dendritic spines of the remaining intrinsic caudate neurons.
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PMID:Attenuation of catecholamine-coupled adenylate cyclase following surgical isolation of rat caudate. 612 17

The effects of a novel compound, 1-(3-chloroanilino)-4-phenylphthalazine (MY-5445), on cyclic nucleotide metabolism and in vitro aggregation of human platelets were investigated. The concentrations of MY-5445 producing 50% inhibition of human platelet aggregation induced by 3 microM ADP, 3 micrograms/ml of collagen and 100 micrograms/ml of arachidonic acid were 0.07, 0.02 and 0.17 microM, respectively. Addition of MY-5445 significantly elevated cyclic GMP content in human platelets but had no effect on cyclic AMP content, suggesting that the drug affects principally the cyclic GMP metabolism in the platelet. Although MY-5445 had no effect on either adenylate cyclase or guanylate cyclase activity, it inhibited specifically human platelet cyclic GMP phosphodiesterase which was separated from cyclic AMP phosphodiesterase by diethylaminoethyl-cellulose column chromatography. The inhibitory effect of MY-5445 on cyclic GMP phosphodiesterase was also demonstrated by direct binding of the enzyme to MY-5445 coupled Sepharose, which was a useful tool for purifying the cyclic GMP phosphodiesterase from human platelet. These results would suggest that MY-5445 inhibits human platelet aggregation by increasing cyclic GMP content and that it provides a useful probe for elucidating the role of cyclic GMP in platelet aggregation.
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PMID:Effect of 1-(3-chloroanilino)-4-phenylphthalazine (MY-5445), a specific inhibitor of cyclic GMP phosphodiesterase, on human platelet aggregation. 614 Dec 86

Cyclic nucleotide metabolism was studied during human monocyte differentiation. Intracellular cAMP increased 17-fold during in vitro differentiation. This increase was due to an increase in the specific activity of adenylate cyclase and a concomitant decrease in the specific activity of cyclic AMP phosphodiesterase. Monocyte adenylate cyclase activity was stimulated by guanine nucleotide, prostaglandin E1, isoproterenol, and epinephrine. Macrophage adenylate cyclase demonstrated less responsiveness to guanine nucleotide and was refractory to stimulation by prostaglandin E1, and to beta-adrenergic receptor agonists. In contrast to cAMP, total intracellular cGMP levels remained constant. Guanylate cyclase was found predominately in the cytosol of monocytes. The specific activity of soluble guanylate cyclase decreased during differentiation, while particulate activity increased more than 40-fold. Cyclic GMP phosphodiesterase activity remained stable during monocyte differentiation. The ratio of cAMP:cGMP increased dramatically from 2:1 in monocytes to 9:1 in macrophages suggesting that cAMP may be an important mediator of differentiation, while cGMP metabolism decreases in the fully differentiated nonproliferating macrophage.
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PMID:Characterization of cyclic nucleotide metabolism during human monocyte differentiation. 614 16

Mepacrine, a phospholipase A2 inhibitor, caused concentration-dependent elevations of cyclic GMP levels without changing cyclic AMP levels in washed rabbit platelets. Mepacrine (100 microM) increased cyclic GMP levels to a peak (25-fold of basal level) within 4 min. Mepacrine had no effect on platelet guanylate cyclase and cyclic AMP phosphodiesterase but selectively inhibited cyclic GMP phosphodiesterase, indicating that mepacrine may elevate platelet cyclic GMP levels as a result of inhibiting cyclic GMP breakdown. In addition, mepacrine accelerated the disaggregation of platelets which had been aggregated maximally by ADP. This effect was associated with elevated cyclic GMP levels. Likewise, sodium nitroprusside and sodium ascorbate, which also elevate platelet cyclic GMP levels, caused marked disaggregation. The increases in cyclic GMP levels with these agents were well correlated with the extent of disaggregation, suggesting that cyclic GMP may mediate a process opposing platelet aggregation and that the mepacrine-induced acceleration of disaggregation may be mediated by cyclic GMP.
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PMID:Mepacrine-induced elevation of cyclic GMP levels and acceleration of reversal of ADP-induced aggregation in washed rabbit platelets. 614 64


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