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

Abstract

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-HT 6 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-HT 6 receptor also finely controls key neuro-developmental 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-HT 6 receptor one of the G proteincoupled 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-HT 6 receptors engage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT 6 -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-HT 6 receptors.

Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

“…Such strong redundancy suggests that loss of ciliary targeting of these receptors is deleterious and evolutionarily selected against. Consistently, mounting evidence indicates that ciliary targeting is critically important for the function of ciliary GPCRs such as Htr6 5,6,9,13,14 .…”

“…All our ciliary trafficking analyses thus far were performed in the kidney epithelial IMCD3 cell line. However, Htr6 and Sstr3 are above all neuronal GPCRs, with Htr6 being expressed exclusively, and Sstr3 mostly, in the central nervous system, where both receptors accumulate in neuronal cilia 5,13 . Thus, our IMCD3 data would be of little significance if they were not also applicable to ciliated neurons in the CNS.…”

“…Remarkably, mice lacking Sstr3, AC3 or cilia in the hippocampus all display very similar learning and memory defects, suggesting that ciliary targeting of Sstr3 and AC3 are essential for these processes 5 . Sstr3 is also expressed outside the brain, mostly in gastrointestinal tract and testes, and is a promising drug target for diabetes and cancer 10-12 . In contrast, serotonin receptor 6 (Htr6) is only expressed in brain, mostly in regions affecting cognition 13 . Drugs targeting Htr6 hold great promise for treatment of disorders such as anxiety, depression, eating disorders, schizophrenia and Alzheimer's disease (AD), and as memory enhancers.…”

“…Although Htr6 also activates Gs-adenylyl cyclase-cAMP signaling, some of its functions are mediated by activation of other effectors such as Cdk5 and the mTOR pathway. Htr6 localizes to neuronal cilia and regulates their length, morphology and composition, effects through which it is reported to affect cognition in a mouse AD model [13][14][15][16] . Thus, it seems very likely that Htr6 ciliary targeting is key for its functions.…”

The 5-HT6 Receptors in the Ventrolateral Orbital Cortex Attenuate Allodynia in a Rodent Model of Neuropathic Pain

“…Mounting evidence suggests that both 5-HT 6 receptor agonists and antagonists display pro-cognitive properties (Hatat et al, 2019;Latacz et al, 2019;Rychtyk et al, 2019;Shahidi et al, 2019), such as improving memory impairment. Similarly, several antipsychotic and antidepressant drugs have high affinity for 5-HT 6 receptors (Kim et al, 2019), and 5-HT 6 receptor agonists and antagonists both induce anxiolytic-and antidepressant-like effects (Yun et al, 2015;Suarez-Santiago et al, 2017;Chaumont-Dubel et al, 2019). Such paradoxical but intriguing findings have ignited tremendous exploration of the underlying molecular signaling.…”