1. μ-opioid and 5-HT1A receptors heterodimerize and show signalling crosstalk via G protein and MAP-kinase pathways
- Author
-
Isabelle Rauly-Lestienne, Didier Cussac, Peter Heusler, Frédéric Finana, Claudie Cathala, Sophie Bernois, and Luc De Vries
- Subjects
MAP Kinase Signaling System ,Receptors, Opioid, mu ,Class C GPCR ,CHO Cells ,Immune receptor ,GTP-Binding Protein alpha Subunits, Gi-Go ,Biology ,Rhodopsin-like receptors ,Cricetulus ,Cricetinae ,Chlorocebus aethiops ,Animals ,Humans ,5-HT5A receptor ,Protease-activated receptor ,Receptor ,Cells, Cultured ,G protein-coupled receptor ,Mitogen-Activated Protein Kinase 1 ,G protein-coupled receptor kinase ,Mitogen-Activated Protein Kinase 3 ,Cell Biology ,Cell biology ,HEK293 Cells ,Biochemistry ,COS Cells ,Receptor, Serotonin, 5-HT1A ,Dimerization - 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.
- Published
- 2012