Opioid control of MAP kinase cascade

Schulz, Rüdiger; Eisinger, Daniela A.; Wehmeyer, Andrea

doi:10.1016/j.ejphar.2004.07.010

Cited by 37 publications

(30 citation statements)

References 35 publications

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“…Although the protective properties of opioid receptors are well established, there is still debate whether their mode of action requires the abovedescribed utilization of the EGFR. In HEK cells, Schulz et al (18) found that ERK activation after opioid receptor stimula- Fig. 3.…”

Section: Discussionmentioning

confidence: 99%

The δ-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation

Förster

Kuno²,

Solenkova³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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The specific δ-opioid receptor agonist [d-Ala2-d-Leu5]enkephalin (DADLE) protects against infarction in the heart when given before ischemia. In rabbit, this protection leads to phosphorylation of the pro-survival kinases Akt and extracellular signal-regulated kinase (ERK) and is dependent on transactivation of the epidermal growth factor receptor (EGFR). DADLE reportedly protects rat hearts at reperfusion. We therefore tested whether DADLE at reperfusion could protect isolated rabbit hearts subjected to 30 min of regional ischemia and 120 min of reperfusion and whether this protection is dependent on Akt, ERK, and EGFR. DADLE (40 nM) was infused for 1 h starting 5 min before reperfusion and reduced infarct size from 31.0 ± 2.3% in the control group to 14.6 ± 1.6% ( P = 0.01). This protection was abolished by cotreatment of the metalloproteinase inhibitor (MPI) and the EGFR inhibitor AG1478. In contrast, 20 nM DADLE, although known to be protective before ischemia, failed to protect. Western blotting revealed that DADLE's protection was correlated to increase in phosphorylation of the kinases Akt and ERK1 and -2 in reperfused hearts (2.5 ± 0.5, 1.6 ± 0.2, and 2.3 ± 0.7-fold of baseline levels, P < 0.05 vs. control). The DADLE-dependent increases in Akt and ERK1/2 phosphorylation were abolished by either MPI or AG1478, confirming a signaling through the EGFR pathway. Additionally, DADLE treatment increased phosphorylation of EGFR (1.4 ± 0.2-fold, P = 0.03 vs. control). Thus the δ-opioid agonist DADLE protects rabbit hearts at reperfusion through activation of the pro-survival kinases Akt and ERK and is dependent on the transactivation of the EGFR.

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Section: Discussionmentioning

confidence: 99%

The δ-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation

Förster

Kuno²,

Solenkova³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…In this study we used primary cultured neurons isolated from mouse striata to address the mechanisms linking mu opioid receptor (MOR) activation to the phosphorylation and activation of the extracellular signal-related kinases 1 and 2 (ERK1/2) members of the MAPK family. Phosphorylation of ERK1/2 by GPCRs involves growth factor receptor transactivation (4). As demonstrated for the ␤-adrenergic receptor, participation of arrestin is an integral part of GPCR signaling through the ERK1/2 signaling pathway in transfected HEK293 cells (6).…”

mentioning

confidence: 99%

“…The mechanisms responsible for the acute changes include G␣ i/o and G␤␥ protein activation that increases potassium conductance, decreases calcium conductance, and results in presynaptic inhibition (1-3). The mechanisms responsible for the long lasting effects of opioids are less clear but may include changes in adenylyl cyclase activity and activation of mitogen activating protein kinase (MAPK) 2 pathways (4,5). In this study we used primary cultured neurons isolated from mouse striata to address the mechanisms linking mu opioid receptor (MOR) activation to the phosphorylation and activation of the extracellular signal-related kinases 1 and 2 (ERK1/2) members of the MAPK family.…”

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confidence: 99%

Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons

Macey

Lowe

Chavkin

2006

Journal of Biological Chemistry

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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.Opioid receptor activation results in both acute and longlasting changes in neuronal physiology. The mechanisms responsible for the acute changes include G␣ i/o and G␤␥ protein activation that increases potassium conductance, decreases calcium conductance, and results in presynaptic inhibition (1-3). The mechanisms responsible for the long lasting effects of opioids are less clear but may include changes in adenylyl cyclase activity and activation of mitogen activating protein kinase (MAPK) 2 pathways (4, 5). In this study we used primary cultured neurons isolated from mouse striata to address the mechanisms linking mu opioid receptor (MOR) activation to the phosphorylation and activation of the extracellular signal-related kinases 1 and 2 (ERK1/2) members of the MAPK family. Phosphorylation of ERK1/2 by GPCRs involves growth factor receptor transactivation (4). As demonstrated for the ␤-adrenergic receptor, participation of arrestin is an integral part of GPCR signaling through the ERK1/2 signaling pathway in transfected HEK293 cells (6). Following agonist activation of MOR, the receptor becomes phosphorylated by G-protein receptor kinase (GRK), which initiates an arrestin-dependent desensitization process that involves clathrin-mediated endocytosis (7). The opioid activation of ERK1/2 by MOR agonist (D-Ala 2 ,Me-Phe 4 ,Gly-ol5) (DAMGO) was demonstrated in MOR-transfected c...

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“…Because HEK293 wt and CHO-K1 cells lack endogenous opioid receptors (Carboni et al, 1997;Schulz et al, 2004), stimulation of mitogenic signaling must be accomplished by the presence of a soluble factor released into the supernatant of HEK/DOR ϪEGFR donor cells in response to DOR activation. GPCRs are able to mediate ERK1/2 signaling via transactivation of multiple RTKs, including the PDGF and IGF-1 receptor (Della Rocca et al, 1999).…”

mentioning

confidence: 99%

Epidermal Growth Factor Treatment Switches δ-Opioid Receptor-Stimulated Extracellular Signal-Regulated Kinases 1 and 2 Signaling from an Epidermal Growth Factor to an Insulin-Like Growth Factor-1 Receptor-Dependent Mechanism

Eisinger¹,

Ammer²

2010

Mol Pharmacol

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]enkephalin (1 M) and etorphine (0.1 M) retained their ability to stimulate ERK1/2 activation. The newly acquired signal transduction mechanism is insensitive to the EGF receptor blockers 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) and N- [4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785), does not involve DOR internalization and activation of the focal adhesion kinase pp125FAK, but requires matrix metalloproteinase-dependent release of soluble growth factors. A supernatant transfer assay in which conditioned growth media of opioid-treated HEK/DOR and HEK/DOR ϪEGFR "donor" cells are used to stimulate ERK1/2 activity in DOR-lacking HEK293 wild type and HEK293ϪEGFR "acceptor" cells revealed that long-term EGF treatment produces a switch in the receptor tyrosine kinase (RTK) system transactivated by opioids. Using microfluidic electrophoresis, chemical inhibitors, phosphorylation-specific antibodies, and EGF receptordeficient Chinese hamster ovary-K1 cells, we identified the release of an insulin-like growth factor-1 (IGF-1)-like peptide and activation of IGF-1 receptors in HEK/DOR ϪEGFR cells after DOR activation. A similar switch from a neurotrophic tyrosine kinase receptor type 1 to an IGF-1 receptor-dependent ERK1/2 signaling was observed for chronically nerve growth factor-treated neuroblastoma ϫ glioma (NG108-15) cells. These results indicate that transactivation of the dominant RTK system in a given cellular setting may represent a general feature of opioids to maintain mitogenic signaling.

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Opioid control of MAP kinase cascade

Cited by 37 publications

References 35 publications

The δ-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation

The δ-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation

Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons

Epidermal Growth Factor Treatment Switches δ-Opioid Receptor-Stimulated Extracellular Signal-Regulated Kinases 1 and 2 Signaling from an Epidermal Growth Factor to an Insulin-Like Growth Factor-1 Receptor-Dependent Mechanism

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