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)

Mammalian rod cyclic nucleotide gated (CNG) channels (i.e., alpha plus beta subunits) are strongly inhibited by phosphatidylinositol 4, 5-bisphosphate (PIP(2)) when they are expressed in Xenopus oocytes and studied in giant membrane patches. Cytoplasmic Mg-ATP inhibits CNG currents similarly, and monoclonal antibodies to PIP(2) reverse the effect and hyperactivate currents. When alpha subunits are expressed alone, PIP(2) inhibition is less strong; olfactory CNG channels are not inhibited. In giant patches from rod outer segments, inhibition by PIP(2) is intermediate. Other anionic lipids (e.g., phosphatidyl serine and phosphatidic acid), a phosphatidylinositol-specific phospholipase C, and full-length diacylglycerol have stimulatory effects. Although ATP also potently inhibits cGMP-activated currents in rod patches, the following findings indicate that ATP is used to transphosphorylate GMP, generated from cGMP, to GTP. First, a phosphodiesterase (PDE) inhibitor, Zaprinast, blocks inhibition by ATP. Second, inhibition can be rapidly reversed by exogenous regulator of G-protein signaling 9, suggesting G-protein activation by ATP. Third, the reversal of ATP effects is greatly slowed when cyclic inosine 5'-monophosphate is used to activate currents, as expected for slow inosine 5' triphosphate hydrolysis by G-proteins. Still, other results remain suggestive of regulatory roles for PIP(2). First, the cGMP concentration producing half-maximal CNG channel activity (K(1/2)) is decreased by PIP(2) antibody in the presence of PDE inhibitors. Second, the activation of PDE activity by several nucleotides, monitored electrophysiologically and biochemically, is reversed by PIP(2) antibody. Third, exogenous PIP(2) can enhance PDE activation by nucleotides.
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PMID:Do phosphatidylinositides modulate vertebrate phototransduction? 1075 30

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.
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PMID:Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. 1091 32

We have shown that endogenous nitrogen oxides (NOx) modulate excitation-contraction coupling in diaphragm. Because cyclic GMP (cGMP) is a second messenger for nitric oxide (NO) inhibition of smooth muscle contraction, we rested the hypothesis that NO acts via cGMP in diaphragm. Fiber bundles from rat diaphragm were studied in vitro. Immunohistochemical analysis using a cGMP-specific monoclonal antibody confirmed the presence of cGMP in the subsarcolemmal region, near nitric oxide synthase (NOS). cGMP measured by ELISA in control muscle (0.27 pmol/mg +/- 0.01 SE) was significantly increased by the NO donor S-nitroso-N-acetylcysteine 1 mM (0.55+/-0.05; N = 6; P < 0.001). Contractile studies showed that the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA) 10 mM increased submaximal (40 Hz) tetanic force (P < 0.0001). L-NNA effects were exaggerated by the guanylate cyclase inhibitor LY83583 5-10 microM; force at 40 Hz was increased (P < 0.001). L-NNA effects were partially reversed by 8-bromo-cGMP 1 mM (8-Br-GMP; a cell-permeable cGMP analogue; P < 0.0001) or dipyridamole 10 microM (DPM; a phosphodiesterase inhibitor; P < 0.0001). 8-Br-GMP and DPM produced more-complete L-NNA reversal in combination (P < 0.0001). We conclude that cGMP functions as a second messenger by which NO inhibits diaphragm contraction.
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PMID:Cyclic GMP is a second messenger by which nitric oxide inhibits diaphragm contraction. 1125 83

A selective and sensitive HPLC measurement of 3',5'-cyclic nucleotide phosphodiesterase (PDE) activity in human platelets using (3,4-dimethoxyphenyl)glyoxal (DMPG) as a fluorogenic reagent for guanine and its nucleosides and nucleotides is described. cGMP, a substrate for PDE, and GMP, which was produced by the enzyme reaction, are selectively converted by the reaction with DMPG to the fluorescent derivatives. The derivatives were separated by reversed-phase HPLC. Human platelet PDE activity was measured and the inhibitory effects of several compounds were investigated.
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PMID:A sensitive assay of human blood platelet cyclic nucleotide phosphodiesterase activity by HPLC using fluorescence derivatization and its application to assessment of cyclic nucleotide phosphodiesterase inhibitors. 1137 82

In vascular tissues including the corpus cavernosum, the organ function is reciprocally regulated by noradrenergic and non-adrenergic, non-cholinergic (NANC) nerves. NANC nerves innervating the corpus cavernosum is thought to be nitroxidergic (nitrergic) nerves which liberate nitric oxide (NO) produced by neuronal NO synthase, and liberated NO activates soluble guanylate cyclase (sGC) in cavernous smooth muscle cells. Intracellular increase in cyclic (c) GMP by activation of sGC dilates cavernous smooth muscle and then induces penile erection. Nitroxidergic (nitrergic) vasodilator nerves also innervate cavernous arteries and veins which regulate the blood volume in the corpus cavernosum. The order of potency of nitroxidergic nerve functions in these tissues (cavernosum > artery >> vein) may be suitable for producing the erection. Therefore, obstruction of the arteries and impairment of nitroxidergic (nitrergic) nerve function are speculated to be one of the causes for erectile dysfunction (ED). On the other hand, NO derived from the cavernous endothelium may partly contribute to erectile function. Sildenafil (Viagra) is one of the potent therapeutics for ED. The agent is a selective phosphodiesterase type 5 (PDE-V) inhibitor that inhibits degradation of cGMP elevated by NO mainly derived from the nerves. To develop more selective and safer therapeutics for ED, further systematic investigations are required.
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PMID:[Nitroxidergic (nitrergic) nerve and erectile dysfunction]. 1186 53

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of the 3'-ester bond of cyclic AMP (cAMP) and cyclic GMP (cGMP), important second messengers in the transduction of a variety of extracellular signals. There is growing interest in the study of PDEs as drug targets for novel therapeutics. We describe the development of a homogeneous fluorescence polarization assay for PDEs based on the strong binding of PDE reaction products (i.e., AMP or GMP) onto modified nanoparticles through interactions with immobilized trivalent metal cations. This assay technology (IMAP) is applicable to both cAMP- and cGMP-specific PDEs. Results of the assay in 384- and 1536-well microplates are presented.
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PMID:A fluorescence polarization assay for cyclic nucleotide phosphodiesterases. 1209 84

Previous studies indicate that cGMP is involved in long-term potentiation (LTP). However, the effects of application of tetanus to induce LTP on cGMP content and the mechanisms by which cGMP may modulate LTP have not been reported. The aim of this work was to study the time course of the changes in cGMP content and of the activity of soluble guanylate cyclase (sGC) (the enzyme that synthesizes cGMP) during LTP. Moreover, we also studied how the changes in cGMP affect cGMP-dependent protein kinase (PKG) and cGMP-degrading phosphodiesterase and the possible role of these changes in LTP. Application of tetanus induced a rise in cGMP, reaching a maximum 10 sec after tetanus. cGMP content decreased below basal levels 5 min after tetanus and remained decreased after 60 min. Activity of sGC increased 5 min after tetanus and returned to basal at 60 min. Tetanus increased the activity of cGMP-degrading phosphodiesterase at 5 and 60 min. GMP, the product of degradation, was increased at 5 and 60 min. Activation of phosphodiesterase and a decrease in cGMP were prevented by inhibiting PKG with Rp-8-bromoguanosine-cGMPS (Rp-8-Br-cGMPS). Inhibition of sGC [with ODQ (oxadiazolo quinoxalin-1-one) or NS 2028 (4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one)], of PKG (with Rp-8-Br-cGMPS), or of cGMP-degrading phosphodiesterase [with zaprinast or MBAM (4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline) ] impairs LTP. The results indicate that induction of LTP involves transient activation of sGC and an increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content.
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PMID:Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. 1245 Nov 12

For deciphering the cyclic guanosine monophosphate (cGMP) signaling pathway, we employed chemical proteomics to identify the novel target molecules of cGMP. We used cGMP that was immobilized onto agarose beads with linkers directed at three different positions of cGMP. We performed a pull-down assay using the beads as baits on tissue lysates and identified 9 proteins by MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight) mass spectrometry. Some of the identified proteins were previously known cGMP targets, including cGMP-dependent protein kinase and cGMP-stimulated phosphodiesterase. Surprisingly, some of the coprecipitated proteins were never formerly reported to associate with the cGMP signaling pathway. The competition binding assays showed that the interactions are not by nonspecific binding to either the linker or bead itself, but by specific binding to cGMP. Furthermore, we observed that the interactions are highly specific to cGMP against other nucleotides, such as cyclic adenosine monophosphate (cAMP) and 5\'-GMP, which are structurally similar to cGMP. As one of the identified targets, MAPK1 was confirmed by immunoblotting with an anti-MAPK1 antibody. For further proof, we observed that the membrane-permeable cGMP (8-bromo cyclic GMP) stimulated mitogen-activated protein kinase 1 signaling in the treated cells. Our present study suggests that chemical proteomics can be a very useful and powerful technique for identifying the target proteins of small bioactive molecules.
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PMID:Identification of novel target proteins of cyclic GMP signaling pathways using chemical proteomics. 1278 86

Large-scale genomic rearrangements including inversions, deletions, and duplications are significant in bacterial evolution. The recently completed Brucella melitensis 16M and Brucella suis 1330 genomes have facilitated the investigation of such events in the Brucella spp. Suppressive subtractive hybridization (SSH) was employed in identifying genomic differences between B. melitensis 16M and Brucella abortus 2308. Analysis of 45 SSH clones revealed several deletions on chromosomes of B. abortus and B. melitensis that encoded proteins of various metabolic pathways. A 640-kb inversion on chromosome II of B. abortus has been reported previously (S. Michaux Charachon, G. Bourg, E. Jumas Bilak, P. Guigue Talet, A. Allardet Servent, D. O'Callaghan, and M. Ramuz, J. Bacteriol. 179:3244-3249, 1997) and is further described in this study. One end of the inverted region is located on a deleted TATGC site between open reading frames BMEII0292 and BMEII0293. The other end inserted at a GTGTC site of the cyclic-di-GMP phosphodiesterase A (PDEA) gene (BMEII1009), dividing PDEA into two unequal DNA segments of 160 and 977 bp. As a consequence of inversion, the 160-bp segment that encodes the N-terminal region of PDEA was relocated at the opposite end of the inverted chromosomal region. The splitting of the PDEA gene most likely inactivated the function of this enzyme. A recombination mechanism responsible for this inversion is proposed.
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PMID:Molecular characterization of Brucella abortus chromosome II recombination. 1452 25

The prognosis of patients with pulmonary arterial hypertension (PAH) is poor. Available therapies (Ca(++)-channel blockers, epoprostenol, bosentan) have limited efficacy or are expensive and associated with significant complications. PAH is characterized by vasoconstriction, thrombosis in-situ and vascular remodeling. Endothelial-derived nitric oxide (NO) activity is decreased, promoting vasoconstriction and thrombosis. Voltage-gated K+ channels (Kv) are downregulated, causing depolarization, Ca(++)-overload and PA smooth muscle cell (PASMC) contraction and proliferation. Augmenting the NO and Kv pathways should cause pulmonary vasodilatation and regression of PA remodeling. Several inexpensive oral treatments may be able to enhance the NO axis and/or K+ channel expression/function and selectively decrease pulmonary vascular resistance (PVR). Oral L-Arginine, NOS' substrate, improves NO synthesis and functional capacity in humans with PAH. Most of NO's effects are mediated by cyclic guanosine-monophosphate (c-GMP). cGMP causes vasodilatation by activating K+ channels and lowering cytosolic Ca++. Sildenafil elevates c-GMP levels by inhibiting type-5 phosphodiesterase, thereby opening BK(Ca). channels and relaxing PAs. In PAH, sildenafil (50 mg-po) is as effective and selective a pulmonary vasodilator as inhaled NO. These benefits persist after months of therapy leading to improved functional capacity. 3) Oral Dichloroacetate (DCA), a metabolic modulator, increases expression/function of Kv2.1 channels and decreases remodeling and PVR in rats with chronic-hypoxic pulmonary hypertension, partially via a tyrosine-kinase-dependent mechanism. These drugs appear safe in humans and may be useful PAH therapies, alone or in combination.
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PMID:The NO - K+ channel axis in pulmonary arterial hypertension. Activation by experimental oral therapies. 1471 30


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