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Simultaneous Activation of the Opioid Receptor (OR)/Sensory Neuron-Specific Receptor-4 (SNSR-4) Hetero-Oligomer by the Mixed Bivalent Agonist Bovine Adrenal Medulla Peptide 22 Activates SNSR-4 but Inhibits OR Signaling

Département de Biochimie et Groupe de Recherche Universitaire sur le Médicament, Université de Montréal, Montréal, Québec, Canada (A.B., M.L., M.B.); and Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York (K.G., L.A.D.)

Hetero-oligomerization among G protein-coupled receptors has been proposed to contribute to signal integration. Because sensory neuron-specific receptors (SNSRs) and the opioid receptors (OR) share a common ligand, the bovine adrenal medulla peptide (BAM) 22, and have opposite effects on pain modulation, we investigated the possible consequences of OR/SNSR-4 hetero-oligomerization on the signaling properties of both receptor subtypes. Bioluminescence resonance energy transfer revealed that the human OR has similar propensity to homo-oligomerize and to form hetero-oligomers with human SNSR-4 when coexpressed in human embryonic kidney 293 cells. The hetero-oligomerization leads to a receptor form displaying unique functional properties. Individual activation of either OR or SNSR-4 in cells coexpressing the two receptors led to the modulation of their respective signaling pathways; inhibition of adenylyl cyclase and activation of phospholipase C, respectively. In contrast, the OR/SNSR-4 bivalent agonist BAM22, which could activate each receptor expressed individually, fully activated the SNSR-4-dependent phospholipase C but did not promote OR-mediated inhibition of adenylyl cyclase in OR/SNSR-4-coexpressing cells. Likewise, concomitant activation of the OR/SNSR-4 hetero-oligomer by selective OR and SNSR-4 agonists promoted SNSR-4 but not OR signaling, revealing an agonist-dependent dominant-negative effect of SNSR-4 on OR signaling. Furthermore, the OR selective antagonist naltrexone trans-inhibited the SNSR-4-promoted phospholipase C activation mediated by BAM22 but not by the SNSR-4-selective agonists, suggesting a bivalent binding mode of BAM22 to the OR/SNSR-4 hetero-oligomer. The observation that BAM22 inhibited the Leu-enkephalin-promoted cAMP inhibition in rat dorsal root ganglia neurons supports the potential physiological implication of such regulatory mechanism.

Address correspondence to: Dr. Michel Bouvier, Département de Biochimie, Université de Montréal, H3C 3J7 Montréal, QC, Canada. E-mail: michel.bouvier{at}umontreal.ca

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