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)

Prenalterol, an allegedly beta 1-selective adrenergic agonist with high intrinsic sympathomimetic activity (ISA), was shown to be weakly lipolytic in rat adipocytes. However, in pertussis-toxin-treated adipocytes, the ISA of prenalterol was markedly increased (from 10-20% to approx. 100% of that of isoprenaline). The cellular sensitivity was also increased (EC50 approx. 60 nM and approx. 3 microM in pertussis-toxin-treated and control cells respectively). A similar effect was seen for other partial agonists such as the beta 2-selective agonist terbutaline and for beta-adrenergic antagonists with some intrinsic activity (metoprolol, pindolol). There was no clear change in sensitivity to isoprenaline's ability to stimulate adenylate cyclase in adipocyte membranes from pertussis-toxin-treated animals but the cyclase activity was increased approx. 4-fold in the presence of 1 microM-GTP. Prenalterol stimulated lipolysis by only small increases in intracellular cyclic AMP (cAMP) levels (less than 10% of that seen with isoprenaline). Basal lipolysis was increased in cells from pertussis-toxin-treated rats and the cellular sensitivity to the non-degradable cAMP analogue, N6-monobutyryl-cAMP, was increased. In control cells, a submaximal concentration of prenalterol (0.1 microM) increased the sensitivity to the cAMP analogues, N6-monobutyryl-cAMP and 8-bromo-cAMP. A low concentration (1 mM) of 8-bromo-cAMP also increased the effect of prenalterol. Similar effects were seen when the phosphodiesterase was inhibited. Thus (1) lipolysis is extremely sensitive to small increases in intracellular cAMP; (2) the degree of activation of adenylate cyclase and thus cAMP formation is the rate-limiting step for the biological response of partial agonists; (3) the inhibitory GTP-binding protein, Gi, is an important modulator ('tissue factor') of the beta-adrenergic agonistic property; (4) low levels of cAMP exert a priming effect on protein kinase A.
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PMID:The inhibitory GTP-binding protein (Gi) regulates the agonistic property of beta-adrenergic ligands in isolated rat adipocytes. Evidence for a priming effect of cyclic AMP. 128 Jan 15

The psychoactive properties of Cannabis sativa and its major biologically active constituent, delta 9-tetrahydrocannabinol, have been known for years. The recent identification and cloning of a specific cannabinoid receptor suggest that cannabinoids mimic endogenous compounds affecting neural signals for mood, memory, movement, and pain. Using whole-cell voltage clamp and the cannabinomimetic aminoalkylindole WIN 55,212-2, we have found that cannabinoid receptor activation reduces the amplitude of voltage-gated calcium currents in the neuroblastoma-glioma cell line NG108-15. The inhibition is potent, being half-maximal at less than 10 nM, and reversible. The inactive enantiomer, WIN 55,212-3, does not reduce calcium currents even at 1 microM. Of the several types of calcium currents in NG108-15 cells, cannabinoids predominantly inhibit an omega-conotoxin-sensitive, high-voltage-activated calcium current. Inhibition was blocked by incubation with pertussis toxin but was not altered by prior treatment with hydrolysis-resistant cAMP analogues together with a phosphodiesterase inhibitor, suggesting that the transduction pathway between the cannabinoid receptor and calcium channel involves a pertussis toxin-sensitive GTP-binding protein and is independent of cAMP metabolism. However, the development of inhibition is considerably slower than a pharmacologically similar pathway used by an alpha 2-adrenergic receptor in these cells. Our results suggest that inhibition of N-type calcium channels, which could decrease excitability and neurotransmitter release, may underlie some of the psychoactive effects of cannabinoids.
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PMID:Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. 131 42

Atopic dermatitis (AD) is characterized by a variety of abnormal physiologic and pharmacologic responses in the skin. Leukocyte abnormalities of the cyclic nucleotide system include increased cAMP phosphodiesterase (PDE) and adenylyl cyclase activities. We have evaluated the possibility that a defect of the inhibitory GTP-binding protein (Gi) might cause inadequate modulation of adenylyl cyclase activity in AD leukocytes. We carried out a series of studies assessing adenylyl cyclase and Gi subunits in monocyte membranes. Using both pertussis toxin ribosylation and direct monoclonal antibody labeling of Gi proteins, we have shown evidence for a decrease or possible absence of one of the Gi proteins in atopic monocyte membranes. A genetic defect or toxin-mediated abnormality in leukocyte membrane Gi could account for these findings. Increased cAMP degradation by PDE may be a compensatory mechanism for increased cAMP synthesis that is regulated by GTP-binding proteins. But this increased PDE activity also rendered AD leukocytes hypo-responsive to immunofunction regulatory signals mediated by cAMP.
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PMID:Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis. 131 24

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

Transducin (T alpha beta gamma), the heterotrimeric GTP-binding protein that interacts with photoexcited rhodopsin (Rh*) and the cGMP-phosphodiesterase (PDE) in retinal rod cells, is sensitive to cholera (CTx) and pertussis toxins (PTx), which catalyze the binding of an ADP-ribose to the alpha subunit at Arg174 and Cys347, respectively. These two types of ADP-ribosylations are investigated with transducin in vitro or with reconstituted retinal rod outer-segment membranes. Several functional perturbations inflicted on T alpha by the resulting covalent modifications are studied such as: the binding of T alpha to T beta gamma to the membrane and to Rh*; the spontaneous or Rh*-catalysed exchange of GDP for GTP or guanosine 5-[gamma-thio]triphosphate (GTP[gamma S]), the conformational switch and activation undergone by transducin upon this exchange, the activation of T alpha GDP by fluoride complexes and the activation of the PDE by T alpha GTP. ADP-ribosylation of transducin by CTx requires the GTP-dependent activation of ADP-ribosylation factors (ARF), takes place only on the high-affinity, nucleotide-free complex, Rh*-T alpha empty-T beta gamma and does not activate T alpha. Subsequent to CTx-catalyzed ADP-ribosylation the following occurs: (a) addition of GDP induces the release from Rh* of inactive CTxT alpha GDP (CTxT alpha, ADP-ribosylated alpha subunit of transducin) which remains associated to T beta gamma; (b) CTxT alpha GDP-T beta gamma exhibits the usual slow kinetics of spontaneous exchange of GDP for GTP[gamma S] in the absence of Rh*, but the association and dissociation of fluoride complexes, which act as gamma-phosphate analogs, are kinetically modified, suggesting that the ADP-ribose on Arg174 specifically perturbs binding of the gamma-phosphate in the nucleotide site; (c) CTxT alpha GDP-T beta gamma can still couple to Rh* and undergo fast nucleotide exchange; (d) CTxT alpha GTP[gamma S] and CTxT alpha GDP-AlFx (AlFx, Aluminofluoride complex) activate retinal cGMP-phosphodiesterase (PDE) with the same efficiency as their unmodified counterparts, but the kinetics and affinities of fluoride activation are changed; (e) CTxT alpha GTP hydrolyses GTP more slowly than unmodified T alpha GTP, which entirely accounts for the prolonged action of CTxT alpha GTP on the PDE; (f) after GTP hydrolysis, CTxT alpha GDP reassociates to T beta gamma and becomes inactive. Thus, CTx catalyzed ADP-ribosylation only perturbs in T alpha the GTP-binding domain, but not the conformational switch nor the domains of contact with the T beta gamma subunit, with Rh* and with the PDE.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Functional modifications of transducin induced by cholera or pertussis-toxin-catalyzed ADP-ribosylation. 133 64

KCl-contracted aortic rings from 18-month-old rats, in contrast with those from 2-month-old rats, showed a substantial reduction in the relaxant effects of the non-selective beta-adrenoceptor agonist, isoproterenol, and of the selective beta 2-adrenoceptor agonist, clenbuterol, without changes in the relaxant actions of forskolin (an activator of the adenylate cyclase), 3-isobutyl-1-methyl-xanthine (a phosphodiesterase inhibitor) or acetylcholine (an endothelium- and cyclic GMP-dependent vasodilator). The relaxant responses induced by adenosine and 2-Cl-adenosine were also reduced in aged aortas. Isoproterenol and cholera toxin (an inhibitor of GTPase activity of the stimulatory GTP-binding protein) reduced cAMP production in aortas from 18-month-old rats. It is suggested that a decrease in the function of the stimulatory GTP-binding protein may contribute at least in part to the impairment in the vasodilation induced by activation of beta-adrenoceptors in aortas from aged rats.
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PMID:Decreased beta-adrenoceptor-mediated vasodilation in aorta from aged rats: possible involvement of a stimulatory GTP-binding protein. 171 50

In order to study the role of individual amino acids in the function of the inhibitory subunit, gamma, of retinal rod phosphodiesterase (PDE), the following substitutions were made: Arg-24----Gly, Lys-29----Thr, Arg-33----Gly, Lys-39----Thr, Lys-41----Thr, Lys-44----Thr, Lys-45----Thr, Glu-77----Gly, and Tyr-84----Ala. Deletion of seven C-terminal amino acids (delta 81-87) was also investigated, and the activity of all the mutant PDE gamma forms determined. Expression of the mutant PDE gamma genes was achieved by sequential in vitro transcription and translation. The results suggest that PDE gamma fragment 24-33, which is rich in basic amino acids, and in particular Arg-24, is essential for PDE gamma binding both to the catalytic subunits (alpha and beta) of phosphodiesterase (PDE alpha beta) and to the alpha-subunit of transducin (T alpha), the GTP-binding protein found in retinal rods that activates cyclic GMP PDE. In contrast, the C-terminal fragment of PDE gamma participates in phosphodiesterase inhibition and in binding to T alpha, but not in binding to PDE alpha beta.
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PMID:Site-directed mutagenesis of the inhibitory subunit of retinal rod cyclic GMP phosphodiesterase. 196 21

The role of 48-kDa protein in visual transduction remains unresolved. Two hypotheses for its role in quenching the light activation of cyclic GMP cascade suggest that the protein binds to either phosphodiesterase or phosphorylated rhodopsin. Since the protein is also reported to bind ATP, we anticipated that the protein may have ATP hydrolyzing activity, and in analogy with the GTP-binding protein of the rod outer segments, such activity may be greatly enhanced by the elements of transduction cyclic GMP cascade, permitting the protein to function cyclically as GTP-binding protein does. We found that purified 48-kDa protein hydrolyzes ATP but at a slow rate of 0.04-0.05 per min. The Km for ATP is about 45-65 microM. The activity is inhibited noncompetitively by ADP with a Ki of about 50 microM. The ATPase activity of 48-kDa protein is not affected by rhodopsin, bleached rhodopsin, phosphorylated rhodopsin, unactivated cyclic GMP phosphodiesterase, or phosphodiesterase (PDE) activated by GMP PNP-bound G-protein. These data show that although 48-kDa protein has ATPase activity, lack of regulation of this activity by the elements of visual transduction makes it unlikely for this activity to have a role in quenching the light activation of cyclic GMP cascade.
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PMID:Photoreceptor rod outer segment 48-kDa protein has ATPase activity. 215 Jul 55

An electropermeabilized preparation of frog retinal rod outer segments (ROS) has been developed to examine the light sensitivity and amplification of visual transduction reactions in a minimally disturbed environment. Electropermeabilized ROS are indistinguishable from whole and osmotically intact ROS in the light microscope and retain 3-fold more protein than mechanically disrupted ROS. They differ from mechanically fragmented ROS in several respects. Illumination results in more amplified activation of the GTP-binding protein transducin (Gt) than previously observed: bleaching as little as approximately 1 rhodopsin molecule (Rho*) in every 10 disks within a single ROS activates 37,000 molecules of Gt per Rho*, equivalent to 70% of the light-activatable Gt present on a single disk face. This amplification is maintained over approximately 1 decade of light intensity but drops sharply as disk faces begin to absorb a second photon. Lower amplification is observed in fragmented ROS and derives from the fact that physical disruption of ROS causes Gt to bind GTP and elute from the membrane, thus decreasing the amount remaining and available for light activation. Illumination of electropermeabilized ROS in the presence of GTP or of the nonhydrolyzable substrate guanosine 5'-(gamma-thio)triphosphate (GTP gamma S) causes redistribution of Gt: an amount (approximately 20 mmol/mol Rho) equivalent to the amount of inhibitory gamma subunit of phosphodiesterase (PDE) remains internal and bound to nucleotide, and the remaining activated Gt diffuses out in a manner graded with light intensity. This suggests that PDE activation by Gt alpha may not require dissociation of Gt alpha bound to the gamma subunit of PDE in a form than can elute from ROS. Two further differences between electropermeabilized and mechanically disrupted ROS are noted: the addition of ATP to electropermeabilized ROS does not affect the light sensitivity or kinetics of the GTP binding reaction, and a specificity for light-induced GTP versus GDP binding is observed.
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PMID:Transducin activation in electropermeabilized frog rod outer segments is highly amplified, and a portion equivalent to phosphodiesterase remains membrane-bound. 216 6

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
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PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76


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