ArticleThe Journal of biological chemistry2009
Src phosphorylation of micro-receptor is responsible for the receptor switching from an inhibitory to a stimulatory signal.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- Opioid-Modulated Receptor Localization and Erk1/2 Phosphorylation in Cells Coexpressing μ-Opioid and Nociceptin Receptors.International journal of molecular sciences · 2023Article
- Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu-opioid receptor.MedComm · 2022Review
- Comprehensive Signaling Profiles Reveal Unsuspected Functional Selectivity of δ-Opioid Receptor Agonists and Allow the Identification of Ligands with the Greatest Potential for Inducing Cyclase Superactivation.ACS pharmacology & translational science · 2021Article
- Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.Pharmacology research & perspectives · 2021Review
- Article
- Post-translational Modifications of Opioid Receptors.Trends in neurosciences · 2020Review
- Phosphorylation of unique C-terminal sites of the mu-opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine.Journal of neurochemistry · 2020Article
- Withdrawal from spinal application of remifentanil induces long-term potentiation of c-fiber-evoked field potentials by activation of Src family kinases in spinal microglia.Neurochemical research · 2018Article
- Src-dependent phosphorylation of μ-opioid receptor at TyrEMBO molecular medicine · 2017Article
- Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation.Anesthesiology · 2017Article
- Site-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Morphine activation of mu opioid receptors causes disinhibition of neurons in the ventral tegmental area mediated by β-arrestin2 and c-Src.Scientific reports · 2017Article
- Gα(i/o)-coupled receptor-mediated sensitization of adenylyl cyclase: 40 years later.European journal of pharmacology · 2015Review
- Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms.Cellular signalling · 2015Article
- Opioid receptor desensitization: mechanisms and its link to tolerance.Frontiers in pharmacology · 2014Review
- β-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia.Handbook of experimental pharmacology · 2014Review
- A novel noncanonical signaling pathway for the μ-opioid receptor.Molecular pharmacology · 2013Article
- Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance.Pharmacological reviews · 2013Review
- Age-Dependent Neuroimmune Modulation of IGF-1R in the Traumatic Mice.Immunity & ageing : I & A · 2012Article
- Ser/ Thr residues at α3/β5 loop of Gαs are important in morphine-induced adenylyl cyclase sensitization but not mitogen-activated protein kinase phosphorylation.The FEBS journal · 2012Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Recent studies have revealed that in G protein-coupled receptor signalings switching between G protein- and beta-arrestin (betaArr)-dependent pathways occurs. In the case of opioid receptors, the signal is switched from the initial inhibition of adenylyl cyclase (AC) to an increase in AC activity (AC activation) during prolonged agonist treatment. The mechanism of such AC activation has been suggested to involve the switching of G proteins activated by the receptor, phosphorylation of signaling molecules, or receptor-dependent recruitment of cellular proteins. Using protein kinase inhibitors, dominant negative mutant studies and mouse embryonic fibroblast cells isolated from Src kinase knock-out mice, we demonstrated that mu-opioid receptor (OPRM1)-mediated AC activation requires direct association and activation of Src kinase by lipid raft-located OPRM1. Such Src activation was independent of betaArr as indicated by the ability of OPRM1 to activate Src and AC after prolonged agonist treatment in mouse embryonic fibroblast cells lacking both betaArr-1 and -2. Instead the switching of OPRM1 signals was dependent on the heterotrimeric G protein, specifically Gi2 alpha-subunit. Among the Src kinase substrates, OPRM1 was phosphorylated at Tyr336 within NPXXY motif by Src during AC activation. Mutation of this Tyr residue, together with mutation of Tyr166 within the DRY motif to Phe, resulted in the complete blunting of AC activation. Thus, the recruitment and activation of Src kinase by OPRM1 during chronic agonist treatment, which eventually results in the receptor tyrosine phosphorylation, is the key for switching the opioid receptor signals from its initial AC inhibition to subsequent AC activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.