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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To establish syntenic relationships of phototransduction genes, we have mapped the genes encoding the alpha-, beta-, and gamma-subunits of rod cGMP phosphodiesterase (PDE) (PDEA, PDEB, PDEG), the alpha'-subunit of cone PDE (PDEA2), and the rod cGMP-gated channel (CNCG) to bovine syntenic groups. The rod cGMP PDE alpha-, beta-, and gamma-subunit genes map to bovine syntenic groups U22, U15 (chromosome 6), and U21 (chromosome 19), respectively. The rod cGMP-gated channel gene also maps to syntenic group U15, and the bovine cone alpha'-subunit gene maps to U26 (chromosome 26). With the exception of the cone PDE alpha'-subunit gene, which has not been mapped in other mammals, all of these genes have been assigned to conserved chromosomal regions shared among bovine, human, and mouse. A compilation of currently known syntenic assignments and predictions regarding future assignments of phototransduction genes in human, mouse, and cattle is presented.
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PMID:Syntenic assignments of visual transduction genes in cattle. 133 Aug 90

The generation of the physiological response of a retinal rod cell to an incident photon involves activation of a cGMP phosphodiesterase (PDE) by a GTP-binding protein, transducin (T). This activation has been shown to occur by formation of a membrane-bound T alpha GTP-PDE complex (Clerc, A., and Bennett, N. (1992) J. Biol. Chem. 267, 6620-6627; Catty, P., Pfister, C., Bruckert, F., and Deterre, P. (1992) J. Biol. Chem 267, 19489-19493). The recovery of the response involves turning-off of T by its intrinsic GTPase activity. We show here that the formation of the membrane-bound T alpha GTP-PDE complex correlates with an enhanced rate of GTP hydrolysis. In vivo, this would provide an appropriate mechanism for fast turn-off of cGMP hydrolysis.
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PMID:Enhanced GTPase activity of transducin when bound to cGMP phosphodiesterase in bovine retinal rods. 133 Oct 45

The cGMP phosphodiesterase (PDE) of retinal rods plays a central role in phototransduction. Illumination leads to its activation by a rod G-protein (Gt, transducin), thus causing a decrease in intracellular cGMP concentration, closure of plasma membrane cationic channels gated by cGMP, and development of the photoresponse. The PDE holoenzyme is an alpha beta gamma 2 tetramer. The alpha- and beta-subunits each contain one catalytic and one, or possibly two, noncatalytic cGMP-binding sites. Two identical gamma-subunits serve as protein inhibitors of the enzyme. Their inhibition is removed when they bind to Gt-GTP during PDE activation. Here we report that the noncatalytic cGMP-binding sites regulate the binding of PDE alpha beta with PDE gamma and as a result determine the mechanism of PDE activation by Gt. If the noncatalytic sites are empty, Gt-GTP physically removes PDE gamma from PDE alpha beta upon activation. Alternatively, if the noncatalytic sites are occupied by cGMP, Gt-GTP releases PDE gamma inhibitory action but remains bound in a complex with the PDE heterotetramer. The kinetic parameters of activated PDE in these two cases are indistinguishable. This mechanism appears to have two implications for the physiology of photoreceptor cells. First, the tight binding of PDE gamma with PDE alpha beta when the noncatalytic sites are occupied by cGMP may be responsible for the low level of basal PDE activity observed in dark-adapted cells. Second, occupancy of the noncatalytic sites ultimately controls the rate of PDE inactivation (cf. Arshavsky, V. Yu., and Bownds, M. D. (1992) Nature 357, 416-417), for the GTPase activity that terminates PDE activity is slower when these sites are occupied and Gt stays in a complex with PDE holoenzyme. In contrast GTPase acceleration is maximal when the noncatalytic sites are empty and Gt-PDE gamma dissociates from PDE alpha beta. Because cGMP levels are known to decrease upon illumination over a concentration range corresponding to the binding constants of the noncatalytic sites, the binding might be involved in determining the lifetime of activated PDE, after a single flash and/or during dark adaptation.
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PMID:Noncatalytic cGMP-binding sites of amphibian rod cGMP phosphodiesterase control interaction with its inhibitory gamma-subunits. A putative regulatory mechanism of the rod photoresponse. 133 60

Cyclic GMP is the second messenger in the phototransduction mechanism in rod photoreceptors. Light-induced activation of cGMP phosphodiesterase (PDE), the hydrolyzing enzyme of cGMP, reduces cytoplasmic cGMP concentration to close the cGMP-activated channel and thereby causes a hyperpolarizing light response. Ca2+ concentration decreases during light-adaptation and this decrease is thought to be at least one of the underlying mechanisms of light-adaptation. Our previous electrophysiological work suggested that PDE in frog rod photoreceptors is regulated by this Ca2+ concentration decrease. In the present work, we isolated a protein that binds to disk membranes at high Ca2+ concentrations. In the presence of this protein (a 26 kDa protein), PDE light sensitivity becomes high at high Ca2+ concentrations. The effect was observed at physiological ranges of Ca2+ concentrations. Thus we could explain high light-sensitivity of photoreceptors under the dark-adapted condition. According to its function, we termed the 26 kDa protein 'sensitivity-modulating protein' or 'S-modulin'. During the purification we noticed that there are additional mechanisms present that may contribute to light-adaptation in frog rod photoreceptors.
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PMID:Light-sensitivity modulating protein in frog rods. 133 15

cDNA clones encoding the beta-subunit of the photoreceptor cGMP phosphodiesterase-(PDE) were isolated from a human retinal library. The encoded polypeptide has 854 amino acid residues with calculated molecular mass of 98416 Da. Alignment of the deduced amino acid sequence with the previously analysed alpha-, beta- and alpha'-subunits of the bovine and mouse PDEs demonstrates highly significant similarities. We have also isolated, from a genomic library, two overlapping recombinant lambda phage clones containing 26 kb of the human PDE beta-subunit gene. The cloning of the human gene and the knowledge of its genomic organization will allow the rapid assessment of the role of this gene in the causation of human retinopathies.
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PMID:[Structural studies of cDNA and the gene for the beta-subunit of cGMP phosphodiesterase from human retina]. 133 85

A genetic selection procedure has been developed which makes the growth of E. coli dependent on expression of a cGMP phosphodiesterase cDNA. E. coli does not contain a cGMP phosphodiesterase, and guanine auxotrophs cannot extract the guanine from cGMP. If a functional cGMP phosphodiesterase is introduced, then guaA auxotrophs will grow on cGMP as a guanine source. The method also selects GMP synthetase cDNAs, which complement the guanine auxotrophy directly. Expression of a Dictyostelium discoideum or human heart cyclic nucleotide phosphodiesterase cDNA permits growth of the E. coli guaA auxotroph in the presence of cGMP. Several commercial cDNA libraries were corrupt and contained phosphodiesterase and/or GMP synthetase sequences that were from a contaminating DNA source.
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PMID:Selection of cDNAs for phosphodiesterases that hydrolyze guanosine 3';5'-monophosphate in Escherichia coli. 134 38

The beta subunit of the cGMP phosphodiesterase (PDE) gene has been identified as the candidate gene for retinal degeneration in the rd mouse. To study the molecular mechanisms underlying degeneration and the potential for gene repair, we have expressed a functional bovine cGMP PDE beta subunit in transgenic rd mice. One transgenic mouse line showed complete photoreceptor rescue across the entire span of the retina. A second independently derived line showed partial rescue in which photoreceptors in the superior but not the inferior hemisphere of the retina were rescued. In the latter animals, intermediate stages of degeneration were observed in the transition zone between rescued and diseased photoreceptors. Pathologic changes in the retina ranged from vesiculation of the basalmost outer segment discs in otherwise structurally intact rod cells to photoreceptors with highly disorganized outer segments and intact inner segments. Totally or partially rescued retinas showed a corresponding restoration of cGMP PDE activity, whereas nonrescued retinas had minimal enzyme activity, characteristic of the rd phenotype. These transgenic animals provide models for studying the molecular basis of retinal degenerative disease and conclusively demonstrate that the phenotype of rd mice is produced by a defect in the beta subunit of cGMP PDE.
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PMID:Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit. 135 91

Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) have been proposed as inhibitory non-adrenergic non-cholinergic (NANC) neurotransmitters in the rat gastric fundus. The smooth muscle relaxant actions of VIP and NO are medaited by cAMP and cGMP, respectively; therefore the effect of inhibitors of phosphodiesterases responsible for cyclic nucleotide breakdown on relaxation induced by VIP, NO and electrical field stimulation was investigated. The non-specific phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), the cGMP-specific phosphodiesterase inhibitor, zaprinast, the adenylate cyclase activator, forskolin, and the cyclic nucleotide analog, 8-bromo cGMP, produced concentration-dependent relaxation of rat gastric fundus strips precontracted by PGF2 alpha. IBMX potentiated isoprenaline-induced relaxation but not relaxation induced by sodium nitroprusside, VIP, NO or electrical field stimulation. Zaprinast potentiated the relaxation induced by sodium nitroprusside, while having no influence on relaxation due to any other stimulus. The combination of both phosphodiesterase inhibitors did not significantly affect the electrically induced relaxation. It is concluded that both cAMP and cGMP mediate relaxation in the rat gastric fundus. Further research is needed to investigate the role of the cyclic nucleotides during NANC relaxation of this tissue.
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PMID:Effect of 3-isobutyl-1-methylxanthine and zaprinast on non-adrenergic non-cholinergic relaxation in the rat gastric fundus. 137 30

The cGMP-specific phosphodiesterase (PDE) of vertebrate retinal rod outer segments (ROS) is a peripheral enzyme activated in vivo by transducin. In vitro artificial activation can be achieved using trypsin. This was described as resulting from degradation of the inhibitory gamma subunit (2 copies/PDE molecule), leaving intact the alpha beta catalytic core. It was, however, observed that trypsin could induce the release of PDE (or solubilization) from the ROS membranes before its activation [Wensel, T. G. & Stryer, L. (1986) Proteins Struct. Funct. Genet. 1, 90-99]. Studying the time course of this solubilization, we were able to purify a trypsin-solubilized PDE still completely inhibited (i.e. with its two gamma subunits bound). The tryptic solubilization of PDE is therefore complete before any functional degradation of the gamma subunits occurs. It was recently suggested that this solubilization could coincide with the cleavage of a C-terminal fragment of the alpha subunit, which can be labeled by methylation of a terminal cysteine residue [Ong, O. C., Ota, I. M., Clarke, S. & Fung, B. K. K. (1989) Proc. Natl Acad. Sci. USA 86, 9238-9242]. We present the following evidence indicating that the C-terminus of the PDE beta subunit is mainly responsible for PDE anchorage to the ROS membrane. (a) The trypsin-solubilized PDE alpha beta gamma 2 has intact blocked N-termini. (b) It is still methylated on PDE alpha. (c) The C-terminus of PDE beta can also be labeled by methylation and its tryptic cleavage coincides well with the PDE solubilization. (d) Sequential cleavage of the alpha and beta polypeptides can also be detected by high-resolution gel electrophoresis: the first cleavage appears on the beta subunit and is completed when cleavage of the alpha subunit begins. The time course for cleavage of the gamma subunits appears to be slower than for the beta subunit and comparable to that of the alpha subunit. Upon longer trypsinization, a 70-kDa polypeptide appears which seems to be a degradation product of PDE beta. Gel-filtration analysis, however, shows that this 70-kDa fragment does not dissociate from the catalytic core.
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PMID:Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis. Role of the C-terminal domain of the beta-subunit. 164 45

Compounds containing the imidazoquinoline nucleus are a new class of potent, broad-spectrum inhibitors of platelet aggregation. This report describes studies with a simply-substituted imidazoquinoline (BMY 20844) and several new ether-linked side chain derivatives (BMY 21638 and BMY 43351). These compounds are potent inhibitors of platelet cAMP phosphodiesterase (IC50 values: BMY 20844, 1.3 X 10(-8); BMY 21638, 2 X 10(-10); and BMY 43351, 1 X 10(-10) M, measured using 0.15 microM cAMP) but have little effect on platelet homogenate cGMP phosphodiesterase (IC50 greater than 10(-5) M). Inhibition of different cAMP phosphodiesterase isozymes was tested to determine if the compounds inhibited similar isozymes in other tissues. Rabbit heart cAMP phosphodiesterase isozymes were resolved by ion-exchange chromatography and three peaks of activity were obtained. BMY 20844 inhibited only fraction III (a "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase) with an IC50 value of 5 X 10(-8) M. These compounds also inhibited canine cardiac sarcoplasmic reticulum membrane-bound "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase with virtually the same potency as inhibition of cAMP phosphodiesterase in platelet homogenate. In washed platelets these compounds elevated cAMP levels and activated the platelet cAMP dependent protein kinase. Activation of cAMP-dependent protein kinase was determined by cAMP-dependent protein kinase ratio measurements and phosphorylation of intracellular proteins. These studies suggest that this potent new class of agents inhibits platelet phosphodiesterase activity in intact platelets causing an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and stimulate protein phosphorylation. This mechanism is, at least in part, responsible for the ability of these compounds to prevent platelet aggregation and thrombosis in experimental animal models.
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PMID:Imidazoquinoline derivatives: potent inhibitors of platelet cAMP phosphodiesterase which elevate cAMP levels and activate protein kinase in platelets. 164 98


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