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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nerve injury results in neuropathic pain, a debilitating pain condition. Whereas cannabinoids are consistently shown to attenuate neuropathic pain, the efficacy of opioids is highly controversial. Molecular mechanisms underlying analgesic effects of opioids and cannabinoids are not fully understood. We have shown that the signaling molecule ERK (extracellular signal-regulated kinase) is activated by C-fiber stimulation in dorsal horn neurons and contributes to pain sensitization. In this study, we examined whether opioids and cannabinoids can affect C-fiber-induced ERK phosphorylation (pERK) in dorsal horn neurons in spinal cord slices from normal and spinal nerve-ligated rats. In normal control spinal slices, capsaicin induced a drastic pERK expression in superficial dorsal horn neurons, which was suppressed by morphine (10 microM), the selective mu-opioid receptor agonist DAMGO [[d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (1 microM)], and the selective CB1 receptor ACEA agonist [arachidonyl-2'-chloroethylamide (5 microM)]. One week after spinal nerve ligation when neuropathic pain is fully developed, capsaicin induced less pERK expression in the injured L(5)-spinal segment. This pERK induction was not suppressed by morphine (10 microM) and DAMGO (1 microM) but was enhanced by high concentration of DAMGO (5 microM). In contrast, ACEA (10 microM) was still very effective in inhibiting capsaicin-induced pERK expression. In the adjacent L(4) spinal segment, both DAMGO and ACEA significantly suppressed pERK induction by capsaicin. These results indicate that, after nerve injury, opioids lose their capability to suppress C-fiber-induced spinal neuron activation in the injured L(5) but not in the intact L(4) spinal segment, whereas cannabinoids still maintain their efficacy.
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PMID:Different effects of opioid and cannabinoid receptor agonists on C-fiber-induced extracellular signal-regulated kinase activation in dorsal horn neurons in normal and spinal nerve-ligated rats. 1622 38

Generalizations of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists in rats were examined. Phencyclidine, MK-801, and ketamine, non-competitive NMDA-receptor antagonists, generalized to the discriminative stimulus effects of U-50,488H, but not those of TRK-820, whereas (+/-)-3-(2-carbaxypiperazine-4-yl) propyl-1-phosphonic acid (CPP), a competitive NMDA-receptor antagonist, and ifenprodil, an NR1/NR2B NMDA-receptor antagonist, did not, suggesting that non-competitive NMDA-receptor antagonists possess U-50,488H-like discriminative stimulus effects in rats. Since U-50,488H and phencyclidine both induce aversive effects, our findings indicate that the cue of the discriminative stimulus effects of U-50,488H and non-competitive NMDA-receptor antagonists may be associated with their aversive effects.
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PMID:Generalization of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists U-50,488H, but not TRK-820 in rats. 1647 3

This study was designed to assess the effects of opiate treatment on the expression of Fas-associated protein with death domain (FADD) in the rat brain. FADD is involved in the transmission of Fas-death signals that have been suggested to contribute to the development of opiate tolerance and addiction. Acute treatments with high doses of sufentanil and morphine (mu-agonists), SNC-80 (delta-agonist), and U50488H (kappa-agonist) induced significant decreases (30-60%) in FADD immunodensity in the cerebral cortex, through specific opioid receptor mechanisms (effects antagonized by naloxone, naltrindole, or nor-binaltorphimine). The cannabinoid CB1 receptor agonist WIN 55,212-2 did not alter FADD content in the brain. Chronic (5 days) morphine (10-100 mg/kg), SNC-80 (10 mg/kg), or U50488H (10 mg/kg) was associated with the induction of tachyphylaxis to the acute effects. In morphine- and SNC-80-tolerant rats, antagonist-precipitated (2 h) or spontaneous withdrawal (24-48 h) induced a new and sustained inhibition of FADD (13-50%). None of these treatments altered the densities of caspases 8/3 (including the active cleaved forms) in the brain. Pretreatment of rats with SL 327 (a selective MEK1/2 inhibitor that blocks ERK activation) fully prevented the reduction of FADD content induced by SNC-80 in the cerebral cortex (43%) and corpus striatum (29%), demonstrating the direct involvement of ERK1/2 signaling in the regulation of FADD by the opiate agonist. The results indicate that mu- and delta-opioid receptors have a prominent role in the modulation of FADD (opposite to that of Fas) shortly after initiating treatment. Opiate drugs (and specifically the delta-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of the antiapoptotic ERK1/2 signaling pathway.
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PMID:Effects of opiate drugs on Fas-associated protein with death domain (FADD) and effector caspases in the rat brain: regulation by the ERK1/2 MAP kinase pathway. 1648 86

The aim of this study was to examine possible interactions of ERK and calcineurin in cardioprotection afforded by delta-opioid receptor stimulation. Infarction was induced in rat hearts by 20-min coronary occlusion and reperfusion. Tissue ERK level and calcienurin activity were determined by immunoblotting and an assay using a phosphopeptide substrate, respectively. Administration of a delta-opioid receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE, 1 mg/kg), before ischemia increased the phospho-ERK levels during ischemia and reduced infarct size (as percentage of risk area, %IS/AR) from 47.7 +/- 2.3% to 23.2 +/- 2.5%. This protection was abolished by 10 mg/kg of natrindole hydrochloride (NTI), a delta-opioid receptor antagonist. PD98059, a MEK1/2 inhibitor, abolished both ERK1/2 activation and infarct size limitation by DADLE. Calcineurin inhibitors, cyclosporine-A (5 mg/kg) and FK506 (3.5 mg/kg), reduced %IS/AR (27.4 +/- 4.4% and 29.9 +/- 3.4%, respectively). The protective effects of these calcineurin inhibitors were inhibited by PD98059, and the combination of DADLE with cyclosporine-A or FK506 did not afford further cardioprotection. DADLE significantly suppressed myocardial calcineurin activity, and this effect was inhibited by NTI. Suppression of calcineurin activity by FK506 was associated with modest activation of ERK1/2. These results suggest that suppression of calcineurin and activation of ERK1/2 are interacting mechanisms involved in cardioprotection by delta-opioid receptor activation.
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PMID:Activation of ERK and suppression of calcineurin are interacting mechanisms of cardioprotection afforded by delta-opioid receptor activation. 1661 6

In this study we investigated the mechanisms responsible for MAP kinase ERK1/2 activation following agonist activation of endogenous mu opioid receptors (MOR) normally expressed in cultured striatal neurons. Treatment with the MOR agonist fentanyl caused significant activation of ERK1/2 in neurons derived from wild type mice. Fentanyl effects were blocked by the opioid antagonist naloxone and were not evident in neurons derived from MOR knock-out (-/-) mice. In contrast, ERK1/2 activation by fentanyl was not evident in neurons from GRK3-/- mice or neurons pretreated with small inhibitory RNA for arrestin3. Consistent with this observation, treatment with the opiate morphine (which is less able to activate arrestin) did not elicit ERK1/2 activation in wild type neurons; however, transfection of arrestin3-(R170E) (a dominant positive form of arrestin that does not require receptor phosphorylation for activation) enabled morphine activation of ERK1/2. In addition, activation of ERK1/2 by fentanyl and morphine was rescued in GRK3-/- neurons following transfection with dominant positive arrestin3-(R170E). The activation of ERK1/2 appeared to be selective as p38 MAP kinase activation was not increased by either fentanyl or morphine treatment in neurons from wild type, MOR-/-, or GRK3-/- mice. In addition, U0126 (a selective inhibitor of MEK kinase responsible for ERK phosphorylation) blocked ERK1/2 activation by fentanyl. These results support the hypothesis that MOR activation of ERK1/2 requires opioid receptor phosphorylation by GRK3 and association of arrestin3 to initiate the cascade resulting in ERK1/2 phosphorylation in striatal neurons.
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PMID:Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons. 1698 18

The advance of functional genomics revealed the superfamily of G-protein coupled receptors (GPCRs). Hundreds of GPCRs have been cloned but many of them are orphan GPCRs with unidentified ligands. The first identified orphan GPCR is the opioid receptor like orphan receptor, ORL1. It was cloned in 1994 during the identification of opioid receptor subtypes and was de-orphanized in 1995 by the discovery of its endogenous ligand, nociceptin or orphanin FQ (N/OFQ). This receptor was renamed as N/OFQ peptide (NOP) receptor. Several selective ligands acting at NOP receptors or other anti-N/OFQ agents have been reported. These include N/OFQ-derived peptides acting as agonists (cyclo[Cys(10),Cys(14)]N/OFQ, [Arg(14), Lys(15)]N/OFQ, [pX]Phe(4)N/OFQ(1-13)-NH(2), UFP-102, [(pF)Phe(4),Aib(7), Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)) or antagonists (Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2), [Nphe(1)]N/OFQ(1-13)-NH(2), UFP-101, [Nphe(1), (pF)Phe(4),Aib(7),Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)), hexapeptides, other peptide derivatives (peptide III-BTD, ZP-120, OS-461, OS-462, OS-500), non-peptide agonists (NNC 63-0532, Ro 64-6198, (+)-5a compound, W-212393, 3-(4-piperidinyl)indoles, 3-(4-piperidinyl) pyrrolo[2,3-b]pyridines) and antagonists (TRK-820, J-113397, JTC-801, octahydrobenzimidazol-2-ones, 2-(1,2,4-oxadiazol-5-yl)-1 H-indole, N-benzyl-D-prolines, SB-612111), biostable RNA Spiegelmers specific against N/OFQ, and a functional antagonist, nocistatin. Buprenorphine and naloxone benzoylhydrazone are two opioid receptor ligands showing high affinity for NOP receptors. NOP receptor agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, and, less promising, in cerebral ischemia and epilepsy, while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. N/OFQ is also involved in cardiovascular, gastrointestinal and immune regulation. Altered plasma levels of N/OFQ have been reported in patients with various pain states, depression and liver diseases. This review summarizes the pharmacological characteristics of, and studies with, the available NOP receptor ligands and their possible clinical implications.
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PMID:Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. 1726 36

MAP kinase is associated with delta-opioid receptor (DOR) signaling and plays a role in cell survival/death. Since anisomycin may alter MAP kinase activity and affect neuronal survival, we investigated whether anisomycin alters neuronal response to hypoxic stress and DOR inhibition. The experiments were performed in cultured cortical neurons. MAP kinase activities were determined by immunoblotting and neuronal viability was assessed by LDH leakage and live/dead morphological study. DOR inhibition with naltrindole (10 microM) led to significant injury in normoxic neurons after 24 h of treatment and exacerbated hypoxia-induced injury. Along with the injury, either by hypoxia or naltrindole, phosphorylated p38 increased in a major way, while phosphorylated ERK and JNK had no significant change or slightly decreased. Anisomycin (50 ng/ml) prevented the increase in phosphorylated p38 immunoreactivity induced by naltrindole and reduced the neuronal injury. The results suggest that (1) MAP kinases are differentially involved in neuronal response to hypoxia and DOR inhibition in cortical neurons with phosphorylated p38 immunoreactivity being upregulated and (2) anisomycin attenuates the increase in phosphorylated p38 immunoreactivity and reduces neuronal injury induced by hypoxia and DOR inhibition.
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PMID:Anisomycin protects cortical neurons from prolonged hypoxia with differential regulation of p38 and ERK. 1739 55

Recent studies have shown that morphine modulates the function of glia cells through both opioid receptor dependent and independent mechanisms. However, the mechanism by which morphine regulates neuronal disorders through the alteration of microglia activity remains unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that both l-morphine and its synthetic stereoenantiomer, d-morphine, an ineffective opioid receptor agonist, significantly reduced LPS- or 1-methyl-4-phenylpyridinium-induced dopaminergic neurotoxicity with similar efficacy, indicating a nonopioid receptor-mediated effect. In addition, using reconstituted neuron and glia cultures, subpicomolar concentrations of morphine were found to be neuroprotective only in the presence of microglia, and significantly inhibited the production of inflammatory mediators from LPS-stimulated microglia cells. Mechanistic studies showed that both l- and d- morphine failed to protect dopaminergic neurons in cultures from NADPH oxidase (PHOX) knockout mice and significantly reduced LPS-induced PHOX cytosolic subunit p47(phox) translocation to the cell membrane by inhibiting ERK phosphorylation. Taken together, our results demonstrate that morphine, even at subpicomolar concentrations, exerts potent anti-inflammatory and neuroprotective effects either through the inhibition of direct microglial activation by LPS or through the inhibition of reactive microgliosis elicited by 1-methyl-4-phenylpyridinium. Furthermore, our study reveals that inhibition of PHOX is a novel site of action for the mu-opioid receptor-independent effect of morphine.
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PMID:Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity. 1761 13

The cellular location of extracellular signal-regulated kinases (ERKs) activated by a G protein-coupled receptor was shown to be dependent on the pathway that mediated their activation. In general, fast activation of ERKs (2 min) mediated by G proteins resulted in the nuclear translocation of phosphorylated ERKs, whereas a slower activation of ERKs (10 min) mediated by beta-arrestins resulted in the cytosolic retention of the phosphorylated ERKs. However, we observed distinct differences from this established ERKs cellular itinerary with the mu-opioid receptor-activated ERKs. Agonists such as morphine and methadone activated ERKs via the protein kinase C-dependent pathway but not the beta-arrestin-dependent pathway. The activated ERKs did not translocate into the nucleus, but phosphorylated 90-kDa ribosomal S6 kinase and induced the activity of transcription factor cAMP response element-binding protein. In contrast, agonists such as etorphine and fentanyl activated ERKs in a beta-arrestin-dependent manner. The phosphorylated ERKs translocated into the nucleus, resulting in increases in Elk-1 activity and GRK2 and beta-arrestin2 transcriptions. Thus, the cellular location of phosphorylated ERKs and subsequent activities on gene transcriptions are dictated by the agonist used to activate the receptor and the subsequent signaling pathway involved.
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PMID:Beta-arrestin-dependent mu-opioid receptor-activated extracellular signal-regulated kinases (ERKs) Translocate to Nucleus in Contrast to G protein-dependent ERK activation. 1794 9

G protein-coupled receptor (GPCR) kinases (GRKs) are key regulators of GPCR function. Here we demonstrate that activation of epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase family, stimulates GRK2 activity and transregulates the function of G protein-coupled opioid receptors. Our data showed that EGF treatment promoted DOR internalization induced by DOR agonist and this required the intactness of GRK2-phosphorylation sites in DOR. EGF stimulation induced the association of GRK2 with the activated EGFR and the translocation of GRK2 to the plasma membrane. After EGF treatment, GRK2 was phosphorylated at tyrosyl residues. Mutational analysis indicated that EGFR-mediated phosphorylation occurred at GRK2 N-terminal tyrosyl residues previously shown as c-Src phosphorylation sites. However, c-Src activity was not required for EGFR-mediated phosphorylation of GRK2. In vitro assays indicated that GRK2 was a direct interactor and a substrate of EGFR. EGF treatment remarkably elevated DOR phosphorylation in cells expressing the wild-type GRK2 in an EGFR tyrosine kinase activity-dependent manner, whereas EGF-stimulated DOR phosphorylation was greatly decreased in cells expressing mutant GRK2 lacking EGFR tyrosine kinase sites. We further showed that EGF also stimulated internalization of mu-opioid receptor, and this effect was inhibited by GRK2 siRNA. These data indicate that EGF transregulates opioid receptors through EGFR-mediated tyrosyl phosphorylation and activation of GRK2 and propose GRK2 as a mediator of cross-talk from RTK to GPCR signaling pathway.
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PMID:EGF transregulates opioid receptors through EGFR-mediated GRK2 phosphorylation and activation. 1846 67


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