title: μ-Opioid and 5-HT1A receptors heterodimerize and show signalling crosstalk via G protein and MAP-kinase pathways.
abstract: μ-opioid receptors have been shown to form heterodimers with several G protein coupled receptors involved in pain regulation such as α(2A)-adrenergic and neurokinin 1 receptors. Because the 5-HT(1A) receptor is also involved in pain control, we investigated whether it can interact with the μ-opioid receptor in cell lines. Using epitope-tagged μ-opioid and 5-HT(1A) receptors, we show that both receptors can co-immunoprecipate when expressed in the same cells. This physical interaction was corroborated by a Bioluminescence Resonance Energy Transfer signal between the μ-opioid receptor fused to Renilla luciferase and the 5-HT(1A) receptor fused to the Green Fluorescent Protein. Consistent with the presence of functional heterodimers, the μ-opioid receptor activated a Gα(o) protein covalently fused to the 5-HT(1A) receptor in membrane preparations as well as a Gα(15) protein fused to the 5-HT(1A) receptor in living cells. We demonstrate that both receptors can coexerce control of the ERK1/2 pathway: for example, μ-opioid receptor-induced ERK1/2 phosphorylation was selectively desensitized by 5-HT(1A) receptor activation. Although 5-HT(1A) and μ-opioid receptors were capable to internalize in response to their own activation, they were ineffective to induce the co-internalization of their partners. Thus, we show a functional heterodimerization of μ-opioid and 5-HT(1A) receptors in cell lines, a complex that might play a role in the control of pain in vivo. These results also support the potential therapeutic action of 5-HT(1A) agonists against nociceptive processes.
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rauly-Lestienne
authors.forename: Peter
authors.initials: P
authors.lastname: Heusler
authors.forename: Frédéric
authors.initials: F
authors.lastname: Finana
authors.forename: Claudie
authors.initials: C
authors.lastname: Cathala
authors.forename: Sophie
authors.initials: S
authors.lastname: Bernois
authors.forename: Luc
authors.initials: L
authors.lastname: De Vries
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D017450:Receptors, Opioid, mu; D044282:Receptor, Serotonin, 5-HT1A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go