Preferential Gs protein coupling of the galanin Gal1 receptor in the μ-opioid-Gal1 receptor heterotetramer

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

Cocaine and several σ receptor ligands inhibit dopamine uptake in rat caudate-putamen

Cocaine and several σ receptor ligands inhibit dopamine uptake via a common site. This is evidenced by a concentration-dependent inhibition of dopamine uptake and displacement of the binding of [ 3H]WIN 35,428 (also called CFT), a cocaine analog with high affinity for the dopamine transporter. Since several σ receptor ligands have been shown to block the stimulant effects of cocaine, this site may serve as a target for future drug development to treat cocaine abuse