Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:7665-99-8 (cGMP)
 21,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3':5'-Cyclic nucleotide phosphodiesterase was isolated from human brain and characterized. After the first stage of purification on phenyl-Sepharose, the enzyme activity was stimulated by Ca2+ and micromolar concentrations of cGMP. High pressure liquid chromatography on a DEAE-TSK-3SW column permitted to identify three ranges of enzymatic activity designated as PDE I, PDE II and PDE III. Neither of the three enzymes possessed a high selectivity for cAMP and cGMP substrates. The catalytic activity of PDE I and PDE II increased in the presence of Ca2+-calmodulin (up to 6-fold); the degradation of cAMP was decreased by cGMP. The Ca2+-calmodulin stimulated PDE I and PDE II activity was decreased by W-7. PDE I and PDE II can thus be classified as Ca2+-calmodulin-dependent phosphodiesterases. With cAMP as substrate, the PDE III activity increased in the presence of micromolar concentrations of cGMP (up to 10-fold), Ca2+ and endogenous calmodulin (up to 2-3-fold). No additivity in the effects of saturating concentrations of these compounds on PDE III was observed. Ca2+ did not influence the rate of cGMP hydrolysis catalyzed by PDE III. In comparison with PDE I and PDE II, the inhibition of PDE III was observed at higher concentrations of W-7 and was not limited by the basal level of the enzyme. These results do not provide any evidence in favour of the existence of several forms of the enzyme in the PDE III fraction. The double regulation of PDE III creates some difficulties for its classification.
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PMID:[3',5'-cyclic nucleotide phosphodiesterase from human brain]. 255 85

S-antigen (48-kDa protein) is a soluble protein of the retina and the pineal gland that is believed to play an important role in the visual process. S-antigen is involved in the regulation of the activity of rod photoreceptor-specific cGMP-phosphodiesterase (cGMP-PDE). The activity of this enzyme has been shown to be deficient in the retina of the rd mouse, which is affected by an autosomal recessive disease characterized by degeneration of the photoreceptor cells. The abnormal cGMP-PDE activity could result from, among other things, a lesion in the enzyme itself or in any of the proteins that regulate it, such as the S-antigen. We have used a mouse cDNA clone for the S-antigen to map the corresponding gene, Sag, to mouse chromosome 1 near Idh-1. Since the rd gene is located on mouse chromosome 5, our results suggest that Sag is not the site of the rd mutation.
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PMID:The gene for retinal S-antigen (48-kDa protein) maps to the centromeric portion of mouse chromosome 1 near Idh-1. 257 83

Extraction of frozen canine cardiac muscle rendered soluble over 90% of the cyclic AMP phosphodiesterase activity. The residual activity was membrane-bound. Ion exchange chromatography of the soluble activity on DE-52 allowed for the resolution of three distinct cyclic AMP phosphodiesterase fractions termed PDE-I, PDE-II and PDE-III in order of elution from the column by a linear NaCl gradient. The relative ratio of cyclic AMP phosphodiesterase activity exhibited by these three peaks was 1:0.65:0.82 and of cyclic GMP phosphodiesterase activity was 1:0.52:0.05 for PDE-I, PDE-II and PDE-III respectively. PDE-II and PDE-III were further purified by re-chromatography on DE-52. Fractions PDE-II and PDE-III were thermolabile at 50 degrees, decaying as single exponentials with half lives of 180 sec and 77 sec respectively. All three species exhibited non-linear Lineweaver-Burke plots for the hydrolysis of cyclic AMP, exhibiting both high and low affinity components. Hydrolysis of cyclic GMP by all three components obeyed normal kinetics, yielding linear plots. PDE-I was a Ca2+/calmodulin-activated species which exhibited a low Km for both cyclic AMP and cyclic GMP but hydrolysed cyclic GMP with a higher Vmax than for cyclic AMP. PDE-II exhibited a much lower Km for cyclic AMP than for cyclic GMP and a much higher Vmax for the hydrolysis of cyclic AMP. PDE-III exhibited a low Km for both cyclic AMP and cyclic GMP, however, its Vmax for cyclic AMP was about 40-fold higher than for cyclic GMP. Cyclic GMP acted as a potent inhibitor (IC50 = 6.3 microM) of cyclic AMP hydrolysis catalysed by PDE-III but not of the hydrolysis of cyclic AMP by PDE-II (IC50 = 33.2 microM). The phosphodiesterase inhibitors milrinone, CI-930, UK-35,493, carbazeran and buquineran acted as potent inhibitors of cyclic AMP hydrolysis catalysed by both PDE-II and PDE-III enzymes. They did not inhibit PDE-I activity. PDE-II, when prepared in the absence of protease inhibitors exhibited a reduced potency to inhibition by these compounds. Treatment of purified PDE-II with trypsin caused a reduction in enzyme activity and reduced dramatically the sensitivity of PDE-II activity to inhibition by these various compounds. The action of proteolysis in attenuating the inhibitory effect of these compounds on PDE-II was most dramatic with CI-930, milrinone, amrinone, buquineran and UK35,493 and least dramatic with carbazeran and IBMX.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Proteolysis of cyclic AMP phosphodiesterase-II attenuates its ability to be inhibited by compounds which exert positive inotropic actions in cardiac tissue. 282 12

We examined the intracellular distribution of three proteins involved in the cyclic GMP cascade of visual transduction; cGMP phosphodiesterase, the alpha-subunit of G-protein and arrestin. In adult rats, light-induced changes in the amounts of G and arrestin in the photoreceptor cell outer segments were observed both by polyacrylamide gel analysis of purified ROS and by immunocytochemical localization on retinal sections. In dark conditions, G was concentrated in the outer segments of photoreceptor cells while in the light G alpha was seen in the inner segments and the outer nuclear layer. Arrestin had the opposite distribution, appearing in the inner segments and outer nuclear layer under dark conditions and in the ROS under light conditions. In contrast, PDE, the enzyme which is activated by G and inhibited by arrestin showed no light-stimulated movement. In both light- and dark-adapted retinas, PDE was localized primarily in the outer segments of the photoreceptor cells.
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PMID:Light-stimulated protein movement in rod photoreceptor cells of the rat retina. 282 35

Two approaches were taken to examine the role which the different forms of phosphodiesterase present in cardiac muscle play in regulating contractility. In an initial study, the effect of selective inhibitors of i) the calmodulin-stimulated phosphodiesterase (M & B 22, 948), ii) the cyclic GMP-stimulated phosphodiesterase (dipyridamole), and iii) the low Km, cyclic AMP-specific phosphodiesterase (imazodan) on the contractility of isolated guinea pig left atria was examined. Of the three selective phosphodiesterase inhibitors, only imazodan increased atrial contractility. In a subsequent study, the effect of imazodan on in vivo contractility was evaluated. Imazodan was found to potently increase contractility in the dog and the Rhesus monkey, while exerting only modest-to-minimal effects of contractility in the guinea pig and the hamster. Imazodan produced no positive inotropic effect in the rat. These species differences can apparently be attributed to i) the presence of subclasses of the low Km, cyclic AMP-specific phosphodiesterase (PDE III) in cardiac muscle, one of which is potently inhibited by the selective PDE III inhibitors imazodan, cyclic GMP and cilostamide, and the other which is selectively inhibited by rolipram and Ro 20-1724, and ii) variations in the intracellular localization of imazodan-sensitive subclass of PDE III. Thus, the maximum inotropic response to imazodan was observed only in those species in which the imazodan-sensitive subclass of PDE III was present and was membrane-bound, e.g., Rhesus monkey and dog. In the dog, the imazodan-insensitive subclass PDE III does not appear to play an important role in regulating cardiac contractility. These observations provide further support for the hypothesis that the inotropic response to imazodan, amrinone and related cardiotonics is due to their inhibitory effects on the cyclic AMP-specific form of phosphodiesterase, and also provides new insight into the relationship between cyclic AMP, phosphodiesterase and myocardial contractility.
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PMID:Multiple molecular forms of phosphodiesterase and the regulation of cardiac muscle contractility. 283 Dec 59

Deficient cGMP-phosphodiesterase (cGMP-PDE) activity results in elevated levels of cGMP in the rd retina before any pathological signs are observed. Since the enzyme is present in rd retina, although it is barely activated by light, we determined whether its synthesis starts at the same time as that of cGMP-PDE in normal retina, or if either its synthesis is halted or degradation of the enzyme increases before the degeneration of the visual cells. We found that synthesis of cGMP-PDE in rd retina is comparable with that in normal retina while the photoreceptors are viable but that cGMP-PDE content is lower than that of normal retina before the visual cells begin to degenerate. Our results suggest that cGMP-PDE is more susceptible to degradation in rd than in normal photoreceptors or, alternatively, that proteolytic enzyme(s) involved in the degradation of cGMP-PDE are in higher concentration or more active in the defective than in the normal retina.
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PMID:Cyclic GMP-phosphodiesterase of rd retina: biosynthesis and content. 283

Cyclic GMP-specific phosphodiesterase (3',5'-cyclic-nucleotide 5'-nucleotidohydrolase, EC 1.3.4.17) (PDE) is thought to be a key enzyme of the retinal-rod phototransduction cyclic nucleotide pathway. We attempted to investigate the properties and content of PDE in retinal-cone photoreceptors. The fractions obtained from cone-dominant ground squirrel retinas were analyzed for cone visual pigment content and PDE activity. The cone visual pigment content was estimated to be approx. 65 pmol per retina. The distribution of cone visual pigment coincided with that of the PDE activity through several steps of photoreceptor membrane purification by sucrose density gradient centrifugation. The ground squirrel retinal PDE was similar to the retinal-rod PDE by its kinetic properties, thermostability, sensitivity to tryptic activation, Stokes radius and pI values. The cone visual pigment enriched fractions contained the heat-stable trypsin-inactivated PDE inhibitor. Its functional properties seem to be similar to those of the retinal-rod PDE inhibitory subunit. The PDE content in ground squirrel retina was roughly estimated to be about five copies of enzyme per 100 cone visual pigment molecules. The obtained results indicated that the major portion of ground squirrel retinal cyclic GMP-specific PDE is the endogenous cone photoreceptor membrane enzyme and strongly supported the conception about the key role of PDE in cone phototransduction. The existence of essential differences between rod and cone systems rapidly returning cyclic GMP-specific amplification cascade components to the dark (or inactivated) states after photon absorption was suggested. If this suggestion is true, the well-known distinctions between response kinetics and light sensitivity of these two kinds of photoreceptor can be explained.
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PMID:Properties and content of cyclic nucleotide phosphodiesterase in photoreceptor outer segments of ground squirrel retina. 283 85

The effects of follicle-stimulating hormone (FSH) and cyclic guanosine 3',5'-monophosphate (cGMP) on spontaneous oocyte maturation and cyclic adenosine 3',5'-cumulus-monophosphate phosphodiesterase activity (cAMP-PDE) were evaluated by using cumulus-oocyte complexes (COCs) from proestrous hamsters. After a 2-h incubation period, FSH (10 micrograms/ml and 1 microgram/ml) reduced the percentage of maturing oocytes compared with controls. This inhibition was partially overcome when cGMP-elevating agents (8-Bromo-cGMP, atrial natriuretic factor or sodium nitroprusside) were included with FSH. After a 3-h period, incubation with FSH and cGMP-elevating agents alone increased the maturation rate above that of the controls. The accelerating effects of cGMP on the maturation rate appear to be caused by its capacity to lower cAMP levels. Combining FSH (1 microgram/ml) with sodium nitroprusside reduced cAMP levels in COCs (not oocytes) compared with groups exposed to FSH alone. FSH increased cGMP levels in COCs in a dose- and time-dependent manner. Both FSH and cGMP-elevating agents produced a dose-dependent increased cAMP-PDE activity in COCs (not oocytes) following a 2-h incubation period. Together, these results suggest that, in vivo, FSH stimulates a rise in both cAMP and cGMP in COCs. While the increase in cAMP may be the initial meiotic trigger, cGMP may serve to subsequently lower cAMP by activating cAMP-PDE and thus permit the maturational process to continue.
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PMID:The effects of follicle-stimulating hormone and cyclic guanosine 3',5'-monophosphate on cyclic adenosine 3',5'-monophosphate-phosphodiesterase and resumption of meiosis in hamster cumulus-oocyte complexes. 285 23

Possible cAMP-dependent and cAMP-independent mechanisms of action for the cardiac effects of OPC-8212, a novel piperazinyl-quinolinone derivative, were evaluated. OPC-8212 was tested for in vitro potency as an inhibitor of soluble bovine cardiac phosphodiesterases using a rapid isolation and assay method involving monoclonal antibodies that distinguish among isozymes. The drug was selective for a low-Km, cGMP-inhibited phosphodiesterase (CGI-PDE) with an IC50 (half-maximal inhibition concentration) of 7.4 mumol/l when measured at a substrate level of 0.35 mumol/l cAMP. Under the conditions used, sulfolane, the solvent for OPC-8212, did not affect CGI-PDE activity. In electrophysiological measurements, OPC-8212 prolonged the action potential duration in canine Purkinje strand preparations up to 148% (APD90) at 10 mumol/l. Concomitantly, OPC-8212 produced a 100% increase in developed force. Both prolongation of the action potential duration and the positive inotropic effect were readily reversed after exposure to tetrodotoxin, 3 mumol/l. Using Na-selective microelectrodes, intracellular Na+ ion activity increased 225% upon exposure to 10 mumol/l OPC-8212. OPC-8212 represents a novel type of positive inotropic agent, possessing both cAMP-dependent (selective PDE isozyme inhibition) and cAMP-independent (activation of intracellular Na+) mechanism of action.
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PMID:Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212. 285 17

Differential and gradient centrifugation of rat brain cerebral cortical homogenates show three cyclic nucleotide phosphodiesterase (CN PDE) activities localized to different subcellular fractions with varying relative specific activities and responsiveness to pharmacologic agents. Type I (calcium/calmodulin-activatable) CN PDE is found primarily in the cytosolic fraction, Type II (cGMP-activatable) CN PDE is predominately membrane associated, and Type IV (cGMP-insensitive) cAMP PDE is distributed equally between soluble and particulate fractions. Fractionation of cerebral cortical membranes shows that Type II and Type IV CN PDE activities reside in synaptosomes. Type II CN PDE is the predominate hydrolytic activity in synaptosomes whereas Type IV cAMP PDE contributes only a small percentage of the total cAMP hydrolysis and Type I CN PDE is not detected in this fraction. The contribution of CN PDE isozymes to the regulation of intracellular cAMP levels was studied using rat brain cortical slices. The rate of cAMP decay in the absence and presence of selective CN PDE inhibitors after adenosine or beta-adrenergic agonist stimulation was determined using an adenine prelabeling technique. These studies show that a rolipram-sensitive, high affinity cAMP PDE (Type IV) is principally responsible for cyclic AMP decay in intact cortical tissue following elevation of cyclic AMP levels by either adenosine or beta-adrenergic receptor agonists. However, this isozyme, which is sensitive to inhibition by rolipram, RO 20-1724 and SQ 65442 contributes only a small percentage of the total cAMP hydrolytic activity in cell-free preparations of cortex.
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PMID:Correlation of cell-free brain cyclic nucleotide phosphodiesterase activities to cyclic AMP decay in intact brain slices. 285 15


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