دورية أكاديمية
Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited.
| العنوان: | Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited. |
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| المؤلفون: | Underwood O; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, Midlands, UK., Fritzwanker S; Institut für Pharmakologie und Toxikologie, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany., Glenn J; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, Midlands, UK., Blum NK; Institut für Pharmakologie und Toxikologie, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany., Batista-Gondin A; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia., Drube J; Institut fur Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany., Hoffmann C; Institut fur Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany., Briddon SJ; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, Midlands, UK., Schulz S; Institut für Pharmakologie und Toxikologie, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.; 7TM Antibodies GmbH, Hans-Knöll-Straße 6, D-07745, Jena, Germany., Canals M; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK. m.canals@nottingham.ac.uk.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, Midlands, UK. m.canals@nottingham.ac.uk. |
| المصدر: | Communications biology [Commun Biol] 2024 Aug 02; Vol. 7 (1), pp. 933. Date of Electronic Publication: 2024 Aug 02. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]- |
| مواضيع طبية MeSH: | beta-Arrestin 2*/metabolism , beta-Arrestin 2*/genetics , Receptors, Opioid, mu*/metabolism , Receptors, Opioid, mu*/genetics, Phosphorylation ; Humans ; HEK293 Cells ; Protein Binding ; Animals ; G-Protein-Coupled Receptor Kinases/metabolism ; G-Protein-Coupled Receptor Kinases/genetics |
| مستخلص: | Desensitisation of the mu-opioid receptor (MOR) is proposed to underlie the initiation of opioid analgesic tolerance and previous work has shown that agonist-induced phosphorylation of the MOR C-tail contributes to this desensitisation. Moreover, phosphorylation is important for β-arrestin recruitment to the receptor, and ligands of different efficacies induce distinct phosphorylation barcodes. The C-tail 370 TREHPSTANT 379 motif harbours Ser/Thr residues important for these regulatory functions. 375 Ser is the primary phosphorylation site of a ligand-dependent, hierarchical, and sequential process, whereby flanking 370 Thr, 376 Thr and 379 Thr get subsequently and rapidly phosphorylated. Here we used GRK KO cells, phosphosite specific antibodies and site-directed mutagenesis to evaluate the contribution of the different GRK subfamilies to ligand-induced phosphorylation barcodes and β-arrestin2 recruitment. We show that both GRK2/3 and GRK5/6 subfamilies promote phosphorylation of 370 Thr and 375 Ser. Importantly, only GRK2/3 induce phosphorylation of 376 Thr and 379 Thr, and we identify these residues as key sites to promote robust β-arrestin recruitment to the MOR. These data provide insight into the mechanisms of MOR regulation and suggest that the cellular complement of GRK subfamilies plays an important role in determining the tissue responses of opioid agonists. (© 2024. The Author(s).) |
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| معلومات مُعتمدة: | AMSPR/1013 United Kingdom AMS_ Academy of Medical Sciences; BB/T013966/1 RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); MRC IMPACT RCUK | Medical Research Council (MRC) |
| المشرفين على المادة: | 0 (beta-Arrestin 2) 0 (Receptors, Opioid, mu) EC 2.7.11.16 (G-Protein-Coupled Receptor Kinases) |
| تواريخ الأحداث: | Date Created: 20240802 Date Completed: 20240802 Latest Revision: 20240807 |
| رمز التحديث: | 20240807 |
| مُعرف محوري في PubMed: | PMC11297201 |
| DOI: | 10.1038/s42003-024-06571-1 |
| PMID: | 39095612 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 2399-3642 |
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| DOI: | 10.1038/s42003-024-06571-1 |