Allosteric modulation of G protein-coupled receptors: from small molecules to heteromeric interactions

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformations readily influenced by their association with ligands and other GPCRs, formerly known as oligomerisation. Originally thought to function as monomers, the actual challenges encompass understanding the mechanism governing these interactions and their relevance in vivo. As for other quaternary arrangements, oligomerisation offers unique allosteric properties. However, unveiling these unappreciated opportunities requires deciphering the molecular basis underlying this phenomenon. Here, we undertook this challenge focusing on the recently identified heteromers between the serotonin 2A and cannabinoid 1 receptors, which have been recently linked to the cognitive side-effects of cannabis. Our results provide new insights into the structural determinants driving cross-talk within this dimer, organised in a rhombus-shape simultaneously recruiting two Gi proteins. This organisation allows non-canonical downstream signalling pathways, which might account for the cognitive impairment induced by marijuana. Furthermore, illustrating the significance of heteromerisation in vivo, we took advantage of the ability of the histamine H3 receptor to modulate aberrant D1R over-activation in Huntington’s disease (HD). Using cellular and murine HD models, we identified functional D1R-H3R heteromers that are lost over HD progression. In addition, striatal cell death was reverted after the administration of H3R ligands. This strategy rescued heteromer expression and prevented both cognitive and motor learning deficits in HD mice, providing compelling evidence of a novel heteromer-based target for HD. Finally, aiming at certain receptor populations through allosteric interactions, we developed 5-HT2CR-selective positive allosteric modulators with anti-obesity properties. For the first time, we identified, validate and delineated a pharmacophore model for the effective targeting of 5-HT2CR allosteric sites, providing an alternative strategy to overcome the often hard to achieve selectivity within receptors subtypes. Altogether, from small molecules to quaternary interactions, our findings provide important insights into the vast array of pharmacological opportunities arising from GPCR allosteric modulation