Preferential Gs protein coupling of the galanin Gal1 receptor in the µ-opioid-Gal1 receptor heterotetramer
Paulo Alexandre de Oliveira, Estefanía Moreno, Nil Casajuana-Martín, Verònica Casadó-Anguera, Ning-Sheng Cai, Gisela Andrea Camacho‐Hernandez, Hu Zhu, Alessandro Bonifazi, Matthew D. Hall, David Weinshenker, Amy Hauck Newman, Diomedes E. Logothetis, Vicent Casadó, Leigh D. Plant, Leonardo Pardo, Sergi Ferré
Abstract
Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal1 receptors (Gal1Rs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and Gal1R when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the Gal1R homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-Gal1R heterotetramer, which is thus bound to Gs via the Gal1R homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.