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: UNIPROT:P51812 (mitogen-activated protein)
10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein (MAP) kinase of Chinese hamster ovary cells (CHO mu66 cell line) transfected to express mu-opioid receptors was markedly activated by mu agonists. The rank order of effectiveness of agonists was approximately the same as the rank order of their binding affinities to the mu receptor. The delta and kappa receptor-specific agonists cyclic[D-Pen2, D-Pen5]enkephalin and U69,593 showed a very weak stimulatory effect. The mu agonist-stimulated MAP kinase activity peaked at approximately 4-8 min and lasted almost 1 hr. The stimulatory effect of mu agonists was antagonized by the opioid receptor antagonist naltrexone and inhibited by pretreatment of cells with pertussis toxin. This opioid-induced activation of MAP kinase activity may have a role in the long term effects of opioids.
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PMID:The stimulatory effect of opioids on mitogen-activated protein kinase in Chinese hamster ovary cells transfected to express mu-opioid receptors. 879 99

The regulation of mitogenic signalling pathways by G-protein-coupled receptors has been studied in Rat-1 fibroblasts stably transfected with the murine delta opioid receptor. We showed recently that stimulation of this receptor led to the activation of the p42 and p44 isoforms of mitogen-activated protein (MAP) kinase [Burt, Carr, Mullaney, Anderson and Milligan (1996) Biochem. J. 320, 227-235]. The present study has examined the role of the ribosomal S6 kinase p70(s6k) in mitogenic signalling by the delta opioid receptor. Treatment of Rat-1 fibroblasts expressing this receptor with the synthetic enkephalin [d-Ala,d-Leu]-enkephalin (DADLE) led to a dose-dependent increase in p70(s6k) enzyme activity. Activation of p70(s6k) was dependent on the level of delta opioid receptor expressed and was sustained above basal levels for several hours. Immunoblotting revealed that p70(s6k) was subject to increased phosphorylation, the extent of which coincided temporally with enzyme activation. Activation of p70(s6k) by DADLE, but not by platelet-derived growth factor, was blocked by pretreatment of cells with pertussis toxin. Activation of p70(s6k) was also partly blocked by wortmannin, indicating that phosphoinositide 3-OH kinase is required for full activation of p70(s6k) by opioid receptor agonists. Activation of the delta opioid receptor in transfected cells led to increased DNA synthesis. This increase was prevented by rapamycin, which also completely blocked activation of p70(s6k) by DADLE. In addition, prevention of the activation of p42 and p44 MAP kinases also blocked the induction of DNA synthesis by DADLE. These results suggest that the activation of both MAP kinases and p70(s6k) might be crucial to the induction of mitogenic responses by Gi-linked receptors such as the delta opioid receptor.
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PMID:Mitogenic signalling by delta opioid receptors expressed in rat-1 fibroblasts involves activation of the p70s6k/p85s6k S6 kinase. 922 49

Morphine sulfate causes immunomodulatory and immunosuppressive effects in human. In this study, the signaling pathway involved in these morphine effects was studied. Addition of morphine sulfate to human CEMx174 lymphocytic cells resulted in increased expression of mitogen-activated protein kinase cascade proteins. Morphine enhanced the cellular levels of ERK1 (44 kDa), ERK2 (42 kDa), a 54-kDa ERK, MEK1 (45 kDa), and MEKK (78 kDa). A time-dependent increase in the activated (Thr and Tyr dually phosphorylated) state of ERK1 and ERK2 was also observed. Naloxone, a morphine antagonist, reversed the observed morphine effects, implicating a micro opioid receptor-mediated process. These findings suggest that mitogen-activated protein kinases are important intermediates in signal transduction pathways initiated by morphine receptors in immune cells.
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PMID:Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. 934 Nov 10

The recently identified 17-amino acid peptide nociceptin (orphanin FQ) is the endogenous ligand for the opioid receptor-like-1 (ORL-1) receptor. A physiologic role for nociceptin (OFQ) activation of the ORL-1 receptor (OFQR) may be to modulate opioid-induced analgesia. The molecular mechanism by which nociceptin (OFQ) and ORL-1 (OFQR) modify opioid-stimulated effects, however, is unclear. Both ORL-1 (OFQR) and opioid receptors mediate pertussis toxin (PTX)-sensitive signal transduction, indicating these receptors are capable of coupling to Gi/Go proteins. This study determines that nociceptin stimulates an intracellular signaling pathway, leading to activation of mitogen-activated protein (MAP) kinase in CHO cells expressing ORL-1 receptor (OFQR). Nociceptin (OFQ)-stimulated MAP kinase activation was inhibited by PTX or by expression of the carboxyl terminus of beta-adrenergic receptor kinase (betaARKct), which specifically blocks Gbetagamma-mediated signaling. Expression of the proline-rich domain of SOS (SOS-PRO), which inhibits SOS interaction with p21ras, also attenuated nociceptin (OFQ)-stimulated MAP kinase activation. The phosphatidylinositol 3-kinase (PI-3K) inhibitors wortmannin and LY294002 reduced nociceptin (OFQ)-stimulated MAP kinase activation, whereas inhibition of protein kinase C (PKC) activity by bisindolylmaleimide I or cellular depletion of PKC had no effect. In a similar manner, in cells expressing mu-opioid receptor, [D-Ala2,N-Me-Phe4,Gly-ol]-enkephalin (DAMGO; a mu-opioid receptor-selective agonist) stimulated PTX-sensitive MAP kinase activation that was inhibited by wortmannin, LY294002, betaARKct expression, or SOS-PRO expression but not affected by inhibition of PKC activity. These results indicate that both ORL-1 (OFQR) and mu-opioid receptors mediate MAP kinase activation via a signaling pathway using the betagamma-subunit of Gi, a PI-3K, and SOS, independent of PKC activity. In cells expressing both ORL-1 (OFQR) and mu-opioid receptors, pretreatment with nociceptin decreased subsequent nociceptin (OFQ)- or DAMGO-stimulated MAP kinase activation. In contrast, pretreatment of cells with DAMGO decreased subsequent DAMGO-stimulated MAP kinase but had no effect on subsequent nociceptin (OFQ)-stimulated MAP kinase activation. These results demonstrate that nociceptin (OFQ) activation of ORL-1 (OFQR) can modulate mu-opioid receptor signaling in a cellular system.
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PMID:Nociceptin (ORL-1) and mu-opioid receptors mediate mitogen-activated protein kinase activation in CHO cells through a Gi-coupled signaling pathway: evidence for distinct mechanisms of agonist-mediated desensitization. 972 27

Delta-opioid receptor (DOR) transcripts and binding sites are expressed by lymphocytes and lymphoid cell lines from several species. Direct modulation of lymphocyte function through DORs affects T cell proliferation, interleukin-2 production, chemotaxis, and intracellular signaling. Moreover, in human DOR-transfected T cells (DOR-Ju.1), delta-opioids have been shown previously to mobilize intracellular calcium rapidly, to inhibit forskolin-stimulated cyclic AMP production, and to activate the mitogen-activated protein kinases ERKs 1 and 2. These observations led us to consider whether delta agonists modify T cell functions, thus affecting the expression of human immunodeficiency virus-1 (HIV-1) by CD4+ T cells. To test this hypothesis, DOR-Ju.1 cells, derived from Jurkat cells stably transfected with a cDNA encoding the neuronal DOR, were stimulated with deltorphin or benzamide, 4-[[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-methoxyphenyl)methyl]N- ,[2S[(S*),2alpha,5beta]]-(9Cl) (SNC-80) prior to the addition of HIV-1. Both deltorphin and SNC-80 concentration-dependently inhibited the production of p24 antigen, an index of HIV-1 expression. Inhibition was maximal with 10(-13)-10(-9) M SNC-80 (>60% reduction) or 10(-15)-10(-11) M deltorphin (>50% reduction). At higher concentrations, less inhibition of p24 antigen production was found. Naltrindole (NTI, 10(-11) M), a selective DOR antagonist, abolished the inhibitory effects of 10(-9) M SNC-80, whereas 10(-13) M NTI partially reversed the effect of SNC-80. Thus, activation of DORs expressed by CD4+ T cells significantly (P < 0.05) reduced the expression of HIV-1 by these cells. These findings suggest that opioid immunomodulation directed at host T cells may be adjunctive to standard antiviral approaches to HIV-1 infection.
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PMID:Delta-opioid suppression of human immunodeficiency virus-1 expression in T cells (Jurkat). 974 64

Previously, we implicated the opioid receptor (OR), Gbetagamma subunits, and Ras in the opioid activation of extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein (MAP) kinase family involved in mitogenic signaling. We now report that OR endocytosis also plays a role in the opioid stimulation of ERK activity. COS-7 and HEK-293 cells were cotransfected with the cDNA of delta-, mu;-, or kappa-OR, dynamin wild-type (DWT), or the dominant suppressor mutant dynamin K44A, which blocks receptor endocytosis. The activation of ERK by opioid agonists in the presence of DWT was detected. In contrast, parallel ectopic coexpression of the K44A mutant with OR, followed by agonist treatment, resulted in a time-dependent attenuation of ERK activation. Immunofluorescence confocal microscopy of delta-OR and DWT-cotransfected COS-7 cells revealed that agonist exposure for 10 min resulted in an ablation of cell surface delta-OR immunoreactivity (IR) and an intensification of cytoplasmic (presumably endosomal) staining as seen in the absence of overexpressed DWT. After 1 hr of delta-agonist exposure the cells displayed substantial internalization of delta-OR IR. If the cells were cotransfected with delta-OR and dynamin mutant K44A, OR IR was retained on the cell surface even after 1 hr of delta-agonist treatment. Parallel immunofluorescence confocal microscopy, using an anti-ERK antibody, showed that agonist-induced time-dependent ERK IR trafficking into perinuclear and nuclear loci was impaired in the internalization-defective cells. Thus, both biochemical and immunofluorescence confocal microscopic evidence supports the hypothesis that the opioid activation of ERK requires receptor internalization in transfected mammalian cells.
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PMID:Requirement of receptor internalization for opioid stimulation of mitogen-activated protein kinase: biochemical and immunofluorescence confocal microscopic evidence. 987 Sep 38

As reports on G protein-coupled receptor signal transduction mechanisms continue to emphasize potential differences in signaling due to relative receptor levels and cell type specificities, the need to study endogenously expressed receptors in appropriate model systems becomes increasingly important. Here we examine signal transduction mechanisms mediated by endogenous kappa-opioid receptors in C6 glioma cells, an astrocytic model system. We find that the kappa-opioid receptor-selective agonist U69,593 stimulates phospholipase C activity, extracellular signal-regulated kinase 1/2 phosphorylation, PYK2 phosphorylation, and DNA synthesis. U69,593-stimulated extracellular signal-regulated kinase 1/2 phosphorylation is shown to be upstream of DNA synthesis as inhibition of signaling components such as pertussis toxin-sensitive G proteins, L-type Ca2+ channels, phospholipase C, intracellular Ca2+ release, protein kinase C, and mitogen-activated protein or extracellular signal-regulated kinase kinase blocks both of these downstream events. In addition, by overexpressing dominant-negative or sequestering mutants, we provide evidence that extracellular signal-regulated kinase 1/2 phosphorylation is Ras-dependent and transduced by Gbetagamma subunits. In summary, we have delineated major features of the mechanism of the mitogenic action of an agonist of the endogenous kappa-opioid receptor in C6 glioma cells.
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PMID:Mitogenic signaling via endogenous kappa-opioid receptors in C6 glioma cells: evidence for the involvement of protein kinase C and the mitogen-activated protein kinase signaling cascade. 1064 7

Opioid tolerance and physical dependence in mammals can be rapidly induced by chronic exposure to opioid agonists. Recently, opioid receptors have been shown to interact with the pertussis toxin (PTX)-insensitive Gz (a member of the Gi subfamily), which inhibits adenylyl cyclase and stimulates mitogen-activated protein kinases (MAPKs). Here, we established stable human embryonic kidney 293 cell lines expressing delta-opioid receptors with or without Gz to examine the role of Gz in opioid receptor-regulated signaling systems. Each cell line was acutely or chronically treated with [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta-selective agonist, in the absence or presence of PTX. Subsequently, the activities of adenylyl cyclase, cyclic AMP (cAMP)-dependent response element-binding proteins (CREBs), and MAPKs were measured by determining cAMP accumulation and phosphorylation of CREBs and the extracellular signal-regulated protein kinases (ERKs) 1 and 2. In cells coexpressing Gz, DPDPE inhibited forskolin-stimulated cAMP accumulation in a PTX-insensitive manner, but Gz could not replace Gi to mediate adenylyl cyclase supersensitization upon chronic opioid treatment. DPDPE-induced adenylyl cyclase supersensitization was not associated with an increase in the phosphorylation of CREBs. Both Gi and Gz mediated DPDPE-induced activation of ERK1/2, but these responses were abolished by chronic opioid treatment. Collectively, our results show that although Gz mediated opioid-induced inhibition of adenylyl cyclase and activation of ERK1/2, Gz alone was insufficient to mediate opioid-induced adenylyl cyclase supersensitization.
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PMID:Regulation of adenylyl cyclase, ERK1/2, and CREB by Gz following acute and chronic activation of the delta-opioid receptor. 1073 27

Agonist-promoted internalization (endocytosis) of G-protein-coupled receptors (GPCRs), including all three opioid receptor types (mu, delta and kappa), has been shown to occur via the clathrin endosomal pathway in response to receptor phosphorylation and the actions of the proteins, beta-arrestin and dynamin. Many members of the GPCR family stimulate mitogen-activated protein kinases (MAPK or ERK) activity and, in several cases, it appears that MAPK activation is dependent on receptor internalization. We have reinvestigated the question of whether internalization is obligatory for MAPK activation by opioid receptors, using cell lines expressing the cloned mu or delta receptor. Morphine, which is known to activate both mu and delta receptors, does not induce their rapid internalization into clathrin-coated endosomes. However, morphine produced a robust stimulation of MAPK in both cell lines, as demonstrated by the appearance of phosphorylated MAPK. Moreover, pre-exposure of cells to the internalization inhibitors, concanavalin A or hypertonic sucrose, totally blocked DAMGO mu-selective agonist) and DTLET (delta-selective agonist)-mediated receptor internalization, yet neither treatment affected MAPK phosphorylation induced by these peptides. Our results provide evidence that receptor internalization is not an obligatory requirement for MAPK activation by mu and delta opioid receptors. Hypotheses are presented to explain the seemingly contradictory results obtained from different laboratories.
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PMID:mu and delta-opioid receptor agonists induce mitogen-activated protein kinase (MAPK) activation in the absence of receptor internalization. 1088 53

Nociceptin is an endogenous peptide that produces its biological effects by binding to the opioid receptor-like (ORL(1)) receptor. It has been shown that activation of ORL(1) receptor leads to inhibition of the adenylyl cyclase activity, but stimulation of the extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases. In this report, we demonstrate that activation of the G protein-coupled ORL(1) receptor in transfected COS-7 cells leads to stimulation of the JNK subgroup of mitogen-activated protein kinases in a Ras/Rac-dependent manner, and it was insensitive to wortmannin. This increased JNK activity was mainly mediated by PTX-sensitive G(i) proteins, and partially contributed by a PTX-insensitive component. Among all known PTX-insensitive G proteins, G(z), G(12), G(14), and G(16) seemed to have functional coupling with the ORL(1) receptor in terms of JNK activation. Stimulation of the endogenous ORL(1) receptor in NG108-15 cells also led to activation of a PTX-sensitive JNK activity in a wortmannin-insensitive manner. The induced JNK activation is accompanied by the active phosphorylation of c-Jun and activating transcription factor-2. This is the first report that demonstrates the stimulatory effect of ORL(1) receptor on JNK, and the subsequent activation of c-Jun and activating transcription factor-2.
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PMID:Regulation of c-Jun N-terminal kinase by the ORL(1) receptor through multiple G proteins. 1108 45


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