The 5-HT6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies

The serotonin (5-HT)(6) receptor is a Gs-coupled receptor exclusively expressed in the central nervous system. Highest receptor densities are found in brain regions implicated in mnemonic functions where the receptor is primarily but not exclusively located in the primary cilium of neurons. The 5-HT6 receptor continues to raise particular interest for neuropharmacologists, given the pro-cognitive effects of antagonists in a wide range of cognitive impairment paradigms in rodents and human. The 5-HT6 receptor also finely controls key neurodevelopmental processes including neuron migration and differentiation. However, its influence upon neurodevelopment and cognition is not solely mediated by its coupling to the Gs-adenylyl cyclase pathway, suggesting alternative signal transduction mechanisms. This prompted studies aimed at characterizing the receptor interactome that identified 125 candidate receptor partners, making the 5-HT6 receptor one of the G protein-coupled receptors with the most extensively characterized interactome. These studies showed that the receptor localization at the plasma membrane and, consequently, its signal transduction, are finely modulated by several receptor partners. They demonstrated that prefrontal 5-HT6 receptors engage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT6-mTOR pathway in temporal epilepsy. Finally, they revealed that the receptor activates Cdk5 signaling in an agonist-independent manner through a mechanism involving receptor phosphorylation by the associated Cdk5 and highlighted its key role in the migration of neurons and neurite growth. These new receptor-operated signaling mechanisms should be considered in the future development of drugs acting on 5-HT6 receptors. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.