Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling

Alexander Samoshkin, Marino Convertino, Chi T. Viet, Jeffrey S. Wieskopf, Oleg Kambur, Jaclyn Marcovitz, Pinkal Patel, Laura S. Stone, Eija Kalso, Jeffrey S. Mogil, Brian L. Schmidt, William Maixner, Nikolay V. Dokholyan, Luda Diatchenko

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number18198
JournalScientific reports
Volume5
DOIs
StatePublished - Dec 11 2015

ASJC Scopus subject areas

  • General

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    Samoshkin, A., Convertino, M., Viet, C. T., Wieskopf, J. S., Kambur, O., Marcovitz, J., Patel, P., Stone, L. S., Kalso, E., Mogil, J. S., Schmidt, B. L., Maixner, W., Dokholyan, N. V., & Diatchenko, L. (2015). Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling. Scientific reports, 5, [18198]. https://doi.org/10.1038/srep18198