Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling
| Autor: | Marino Convertino, Oleg Kambur, Nikolay V. Dokholyan, Chi T. Viet, Eija Kalso, Luda Diatchenko, Jeffrey S. Wieskopf, Laura S. Stone, Pinkal Patel, Brian L. Schmidt, Jeffrey S. Mogil, William Maixner, Alexander Samoshkin, Jaclyn Marcovitz |
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| Přispěvatelé: | Medicum, Department of Pharmacology, Clinicum, Eija Kalso / Principal Investigator, Department of Diagnostics and Therapeutics, Anestesiologian yksikkö |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Models Molecular Molecular Conformation Receptors Opioid mu Gene Expression Ligands BETA(2)-ADRENERGIC RECEPTOR Mice MOR-1 SPLICE VARIANTS GABA(B) RECEPTORS 0302 clinical medicine Receptor BETA-2-ADRENERGIC RECEPTOR Neurons Multidisciplinary Transmembrane protein 3. Good health Cell biology Analgesics Opioid Hyperalgesia medicine.symptom Signal transduction CHRONIC PAIN medicine.drug Protein Binding Signal Transduction Gene isoform medicine.medical_specialty Cell signaling Adrenergic receptor Biology Article 03 medical and health sciences Structure-Activity Relationship Internal medicine medicine Animals Humans DISCRETE MOLECULAR-DYNAMICS THERAPEUTIC TARGET MORPHINE-TOLERANCE 3126 Surgery anesthesiology intensive care radiology RHEUMATOID-ARTHRITIS 030104 developmental biology Endocrinology Opioid RAT Calcium Ganglia Receptors Adrenergic beta-2 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy. |
| Databáze: | OpenAIRE |
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