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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.

Received for publication January 24, 2006.

Accepted for publication May 8, 2006.

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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