ArticleThe Journal of biological chemistry2012
GRK2 protein-mediated transphosphorylation contributes to loss of function of μ-opioid receptors induced by neuropeptide FF (NPFF2) receptors.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 42 citations in OpenAlex.
- Local GPCR density tips the balance of μ-opioid receptor trafficking.bioRxiv : the preprint server for biology · 2026Article
- Review
- Opioid receptors signaling network.Journal of cell communication and signaling · 2022Article
- Double life: How GRK2 and β-arrestin signaling participate in diseases.Cellular signalling · 2022Review
- HA-MOP knockin mice express the canonical µ-opioid receptor but lack detectable splice variants.Communications biology · 2021Article
- 5-HTMolecular psychiatry · 2019Article
- Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress.Journal of molecular medicine (Berlin, Germany) · 2019Review
- Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists.Science signaling · 2019Article
- Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease.JACC. Basic to translational science · 2018Review
- Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes.Cardiovascular research · 2017Article
- Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via Gβγ/PKC/ERK1/2 pathway and heterologous receptor desensitization.Scientific reports · 2017Article
- Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain.Molecular pharmacology · 2015Article
- Different mechanisms of homologous and heterologous μ-opioid receptor phosphorylation.British journal of pharmacology · 2015Review
- Identification and functional characterization of the phosphorylation sites of the neuropeptide FF2 receptor.The Journal of biological chemistry · 2014Article
- Nonpeptide small molecule agonist and antagonist original leads for neuropeptide FF1 and FF2 receptors.Journal of medicinal chemistry · 2014Article
- Heterologous regulation of Mu-opioid (MOP) receptor mobility in the membrane of SH-SY5Y cells.The Journal of biological chemistry · 2014Article
- Evaluation of commercial antibodies against human sphingosine-1-phosphate receptor 1.Naunyn-Schmiedeberg's archives of pharmacology · 2014Article
- Involvement of Mammalian RF-Amide Peptides and Their Receptors in the Modulation of Nociception in Rodents.Frontiers in endocrinology · 2014Review
- Opioid receptor desensitization: mechanisms and its link to tolerance.Frontiers in pharmacology · 2014Review
- Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration.Molecular pharmacology · 2013Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neuropeptide FF (NPFF) interacts with specific receptors to modulate opioid functions in the central nervous system. On dissociated neurons and neuroblastoma cells (SH-SY5Y) transfected with NPFF receptors, NPFF acts as a functional antagonist of μ-opioid (MOP) receptors by attenuating the opioid-induced inhibition of calcium conductance. In the SH-SY5Y model, MOP and NPFF(2) receptors have been shown to heteromerize. To understand the molecular mechanism involved in the anti-opioid activity of NPFF, we have investigated the phosphorylation status of the MOP receptor using phospho-specific antibody and mass spectrometry. Similarly to direct opioid receptor stimulation, activation of the NPFF(2) receptor by [D-Tyr-1-(NMe)Phe-3]NPFF (1DMe), an analog of NPFF, induced the phosphorylation of Ser-377 of the human MOP receptor. This heterologous phosphorylation was unaffected by inhibition of second messenger-dependent kinases and, contrarily to homologous phosphorylation, was prevented by inactivation of G(i/o) proteins by pertussis toxin. Using siRNA knockdown we could demonstrate that 1DMe-induced Ser-377 cross-phosphorylation and MOP receptor loss of function were mediated by the G protein receptor kinase GRK2. In addition, mass spectrometric analysis revealed that the phosphorylation pattern of MOP receptors was qualitatively similar after treatment with the MOP agonist Tyr-D-Ala-Gly (NMe)-Phe-Gly-ol (DAMGO) or after treatment with the NPFF agonist 1DMe, but the level of multiple phosphorylation was more intense after DAMGO. Finally, NPFF(2) receptor activation was sufficient to recruit β-arrestin2 to the MOP receptor but not to induce its internalization. These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex.
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