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

Sci Rep. 2015 Dec 11;5:18198. doi: 10.1038/srep18198.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Animals
  • Calcium / metabolism
  • Ganglia / metabolism
  • Gene Expression
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Neurons / metabolism
  • Protein Binding
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*
  • Signal Transduction*
  • Structure-Activity Relationship

Substances

  • Analgesics, Opioid
  • Ligands
  • Receptors, Adrenergic, beta-2
  • Receptors, Opioid, mu
  • Calcium