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)

This study determined whether phosphodiesterase (PDE) was activated by protein kinase C (PKC) upon kappa-receptor stimulation, and if so, to identify the isozyme. We first studied the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulphonate (U50,488H), a selective kappa-opioid receptor (OR) agonist, and phorbol-12-myristate-13-acetate (PMA), a PKC activator, on cAMP accumulation and PDE activity in rat ventricular myocytes when PKC and PDE were inhibited by respective inhibitors. Like PMA, U50,488H decreased the forskolin-stimulated cAMP accumulation and dose-dependently stimulated the PDE activity, which were antagonized by 10(-6) M chelerythrine and bisindolylmaleimide I, selective PKC antagonists. In addition, 3-isobutyl-1-methylxanthine, a PDE inhibitor, dose-dependently attenuated the inhibition on forskolin-stimulated cAMP accumulation and abolished the stimulation on PDE activity by U50,488H and PMA. The observations suggest that PKC may enhance cAMP degradation through activating PDE upon kappa-OR stimulation. To identify the isozyme(s) mediating the effect of PKC upon kappa-OR stimulation, selective inhibitors were used. We found that 10(-5) M Ro-20-1724, a selective cAMP-specific PDE (PDE-IV) inhibitor, abolished the inhibitory effects of U50,488H and PMA, whereas 8-methoxymethyl-3-isobutyl-1-methylxanthine, erythro-9-(2-hydroxy-3-nonyl) adenine, cilostamide, and zaprinast, selective inhibitors of Ca(2+)/calmodulin-dependent PDE (PDE-I), cGMP-stimulated PDE (PDE-II), cGMP-inhibited PDE (PDE-III), and cGMP-specific PDE (PDE-V), respectively, had no effect. Moreover, rolipram, another selective PDE-IV inhibitor, also dose-dependently attenuated the inhibition on forskolin-stimulated cAMP accumulation and stimulation on PDE activity by U50,488H and PMA. In conclusion, this study has provided evidence for the first time that PKC and PDE-IV mediate the action of kappa-OR.
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PMID:The role of phosphodiesterase in mediating the effect of protein kinase C on cyclic AMP accumulation upon kappa-opioid receptor stimulation in the rat heart. 1068 24

The present study was designed to examine the roles of protein kinase C (PKC) and phosphodiesterase (PDE) in modulating the action of kappa receptor stimulation on cAMP accumulation in isolated iris-ciliary bodies (ICBs) of New Zealand White rabbits. The kappa receptor agonist, (+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine (BRL-52537) (BRL), and the PKC activator, phorbol 12,13-dibutyrate (PDBu), both caused a concentration-dependent inhibition of forskolin-stimulated cAMP production. The inhibitory effect of BRL on cAMP levels was significantly reduced in the presence of the selective kappa receptor antagonist, norbinaltorphimine (10(-6) M), but the effect of PDBu was not, thus supporting the involvement of kappa-opioid receptors in the response to BRL. In the presence of 3-isobutyl-1-methylxanthine or rolipram (10(-5) M), the inhibitory effect of BRL or PDBu (10(-6) M) on cyclic AMP accumulation was abolished. In the presence of the selective PKC antagonist, chelerythrine (10(-6) M), the inhibitory effect of PDBu or BRL (10(-6) M) was significantly reduced. Direct measurement of PDE activity demonstrated the ability of BRL and PDBu (10(-6) M) to augment the activity of these enzymes. Preincubation of ICBs with rolipram (10(-5) M) or chelerythrine (10(-6) M) caused significant reversal of both BRL- and PDBu-induced increases in PDE activity. These results indicate that stimulation of PKC and PDE4 activity is part of the complex mechanism whereby kappa-opioid receptor agonists reduce levels of cAMP in the rabbit ICB. This mechanism of action could contribute to the ability of kappa-opioid agonists to suppress aqueous flow rate and to lower intraocular pressure.
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PMID:Inhibition of cAMP accumulation by kappa-receptor activation in isolated iris-ciliary bodies: role of phosphodiesterase and protein kinase C. 1196 Oct 62

Responses to opioid agonists vary, depending on past opioid exposure and the physiological state. The intracellular signaling pathway mediated by cAMP and protein kinase A (PKA) has been linked to regulation of opioid receptor responsiveness. The role of the cAMP-PKA pathway in regulating opioid receptor gene expression is incompletely defined. Mu-opioid receptor (MuOR) and orphanin FQ/nociceptin receptor (ORL(1)) transcripts were measured after activating this pathway in human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were maintained in continuous monolayer culture. Cells were incubated with combinations of agents which activate the cAMP-PKA signal transduction pathway, including forskolin and choleratoxin (CTX). MuOR and ORL(1) transcript levels were measured by hybridization to specific probes. Activation of the cAMP-PKA signal transduction pathway with forskolin in the presence of phosphodiesterase inhibitors was associated with a time-dependent decrease in the level of MuOR mRNA; partial recovery was observed with prolonged incubations. Forskolin effects were mimicked by CTX, but not by dideoxyforskolin. The PKA inhibitor H89 blunted the actions of forskolin. However, forskolin responses persisted despite coincubation with protein synthesis inhibitors. ORL(1) transcript levels did not significantly change, but vasoactive intestinal polypeptide (VIP) transcripts exhibited substantial increases, in the presence of forskolin or CTX. These observations support a role for cAMP in regulating MuOR responsiveness through actions at the level of receptor gene expression. ORL(1) transcript levels are not effected, suggesting that the cAMP-PKA pathway has differential effects on the expression of mRNA for different, but biochemically closely related, opioid receptor subtypes.
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PMID:Orphanin FQ/nociceptin and mu-opioid receptor mRNA levels in human SH-SY5Y neuroblastoma cells: effects of activating the cAMP-PKA signal transduction pathway. 1210 67

Agonist exposure of many G protein-coupled receptors induces a rapid receptor phosphorylation and uncoupling from G proteins. Resensitization of these desensitized receptors requires endocytosis and subsequent dephosphorylation. Using a yeast two-hybrid screen, the rat mu-opioid receptor (MOR1, also termed MOP) was found to be associated with phospholipase D2 (PLD2), a phospholipid-specific phosphodiesterase located in the plasma membrane, which has been implicated in the formation of endocytotic vesicles. Coimmunoprecipitation experiments in HEK293 cells coexpressing MOR1 and PLD2 confirmed that MOR1 constitutively interacts with PLD2. Treatment with the mu receptor agonist DAMGO ([d-Ala(2), Me Phe(4), Glyol(5)]enkephalin) led to an increase in PLD2 activity, whereas morphine, which does not induce MOR1 receptor internalization, failed to induce PLD2 activation. The DAMGO-mediated PLD2 activation was inhibited by brefeldin A, an inhibitor of ADP-ribosylation factor (ARF) but not by the protein kinase C (PKC) inhibitor calphostin C indicating that opioid receptor-mediated activation of PLD2 is ARF- but not PKC-dependent. Furthermore, heterologous stimulation of PLD2 by phorbol ester led to an accelerated internalization of the mu-opioid receptor after both DAMGO and morphine exposure. Conversely the inhibition of PLD2-mediated phosphatidic acid formation by 1-butanol or overexpression of a negative mutant of PLD2 prevented agonist-mediated endocytosis of MOR1. Together, these data suggest that PLD2 play a key role in the regulation of agonist-induced endocytosis of the mu-opioid receptor.
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PMID:ADP-ribosylation factor-dependent phospholipase D2 activation is required for agonist-induced mu-opioid receptor endocytosis. 1251 90

Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50-200 microg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1-10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 microg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 microg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N(G)-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation.
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PMID:Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine. 1257 11

There are only a few studies on the molecular mechanisms underlying the peripheral antihyperalgesic effect of opioids. The aim of this study was to investigate the molecular bases of the peripheral antihyperalgesic effect of fentanyl in a model of prostaglandin-induced chemical hyperalgesia. Prostaglandin E2 (1.4 nmol) injected into one hind paw of male Wistar rats (200-250 g, N = 6 in each experimental or control group) pretreated with indomethacin (2.5 mg/kg) potentiated the nocifensive response to formalin (1%) injection made 60 min later. Drugs applied locally 30 min after prostaglandin E2 induced the following effects: fentanyl (0.1-1.0 nmol) caused a dose-dependent reversal of the hyperalgesic state, naloxone (2 nmol) co-injected with fentanyl (1 nmol) completely reversed the antihyperalgesic effect, Nomega-nitro-L-arginine (NOARG, 0.05-0.2 mol) in combination with fentanyl (1.0 nmol) caused a dose-dependent inhibition of the antihyperalgesic effect of fentanyl, co-administration of L-arginine (0.5 mol) with NOARG (0.2 mol) plus fentanyl (1.0 nmol) fully restored the antihyperalgesic effect, and the cyclic-GMP phosphodiesterase inhibitor UK-114,542-27 (5-[2-ethoxy-5-(morpholinylacetyl) phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo [4,3-d]-pyrimidin-7-one methanesulfonate monohydrate; 0.5-2.0 mol) potentiated a subeffective dose of fentanyl (0.1 nmol) in a dose-dependent manner. However, UK-114,542-27 (2.0 mol) injected alone did not produce this antihyperalgesic effect. Systemically administered fentanyl (1.0 nmol, sc) did not cause antinociception. Taken together, these results support the view that fentanyl reverses prostaglandin E2-induced hyperalgesia, probably by activating an opioid receptor at the periphery, and furthermore the L-arginine/nitric oxide/cyclic-GMP pathway may mediate this peripheral effect of fentanyl.
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PMID:The L-arginine/nitric oxide/cyclic-GMP pathway apparently mediates the peripheral antihyperalgesic action of fentanyl in rats. 1466 55

Most mu-opioid receptor agonists recruit beta-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of beta-arrestin2. To resolve this paradox, we examined the effects of morphine and fentanyl in acute brain slices of the locus coeruleus and the periaqueductal gray from beta-arrestin2 knockout mice. We report that, in these mice, presynaptic inhibition of evoked inhibitory postsynaptic currents was enhanced, whereas postsynaptic G protein-coupled K(+) (Kir3/GIRK) currents were unaffected. The frequency, but not amplitude, of miniature inhibitory postsynaptic currents was increased in beta-arrestin2 knockout mice, indicating a higher release probability compared to WT mice. The increased release probability resulted from increased cAMP levels because of impaired phosphodiesterase 4 function and conferred an enhanced efficacy of morphine to inhibit GABA release. Thus, beta-arrestin2 attenuates presynaptic inhibition by opioids independent of mu-opioid receptor-driven recruitment, which may make beta-arrestin2 a promising target for regulating analgesia.
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PMID:beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids. 1571 84

PACAP is a peptide with neuroprotective activity, which induces adenylate cyclase and protein kinase A (PKA) activity. PACAP has also been shown to induce neurite outgrowth in PC12 cells and dorsal root ganglion (DRG) neurons. Here, we report that exogenous PACAP38 promotes neurite outgrowth in the F11 neuroblastoma/dorsal DRG hybrid cell line. Using an automated microscopy system, we show that PACAP38 induces a 170-fold increase in neurite length, with an EC50 of 3.1 nM, compared to 3.7 microM for forskolin and 143.4 microM for dibutyril cyclic AMP (dbcAMP). PACAP38 induced a 4-fold increase in the level of phosphorylation of cAMP-responsive element binding protein (CREB) in F11 cells with an EC50 of 130 pM. In contrast a peptide related to PACAP, vasoactive intestinal peptide (VIP) failed to induce CREB phosphorylation or neurite outgrowth in F11 cells. Addition of the nonselective phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX) increased the potency of PACAP at inducing neurite outgrowth by ten-fold. The PKA inhibitor, H89, was a potent inhibitor of PACAP38-induced neurite outgrowth. The delta-opioid receptor agonist, SNC 80, did not inhibit PACAP-induced neurogenesis even though it did reduce CREB phosphorylation. In contrast to previous studies in PC12 cells, PACAP38 failed to show MEK1 activation in F11 cells. PACAP is upregulated in DRG neurons as a result of injury, and F11 cells provide an easily accessible in vitro model for understanding mechanisms underlying PACAP differentiation and neurogenesis.
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PMID:Pituitary adenylate cyclase-activating peptide (PACAP) induces differentiation in the neuronal F11 cell line through a PKA-dependent pathway. 1648 95

We have recently shown that the mu-opioid receptor [MOR1, also termed mu-opioid peptide (MOP) receptor] is associated with the phospholipase D2 (PLD2), a phospholipid-specific phosphodiesterase located in the plasma membrane. We further demonstrated that, in human embryonic kidney (HEK) 293 cells co-expressing MOR1 and PLD2, treatment with (D-Ala2, Me Phe4, Glyol5)enkephalin (DAMGO) led to an increase in PLD2 activity and an induction of receptor endocytosis, whereas morphine, which does not induce opioid receptor endocytosis, failed to activate PLD2. In contrast, a C-terminal splice variant of the mu-opioid receptor (MOR1D, also termed MOP(1D)) exhibited robust endocytosis in response to both DAMGO and morphine treatment. We report here that MOR1D also mediates an agonist-independent (constitutive) PLD2-activation facilitating agonist-induced and constitutive receptor endocytosis. Inhibition of PLD2 activity by over-expression of a dominant negative PLD2 (nPLD2) blocked the constitutive PLD2 activation and impaired the endocytosis of MOR1D receptors. Moreover, we provide evidence that the endocytotic trafficking of the delta-opioid receptor [DOR, also termed delta-opioid peptide (DOP) receptor] and cannabinoid receptor isoform 1 (CB1) is also mediated by a PLD2-dependent pathway. These data indicate the generally important role for PLD2 in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor (GPCR) endocytosis.
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PMID:Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors. 1653 74

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.
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PMID:Roles of opioid receptor subtypes on the antinociceptive effect of intrathecal sildenafil in the formalin test of rats. 1858 61


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