Serotonin 5-HT<sub>2C</sub> Receptor Signaling Analysis Reveals Psychedelic Biased Agonism.
Abstract
The serotonin 2C receptor (5-HT<sub>2C</sub>) is a G protein-coupled receptor implicated in multiple physiological and psychological processes and has been investigated as a therapeutic target for neuropsychiatric conditions such as obesity, drug abuse, and depression. With renewed interest in serotonergic psychedelics for treating depression, 5-HT<sub>2C</sub> may contribute to psychedelic-induced therapeutic effects. Despite earlier evidence of 5-HT<sub>2C</sub> G protein coupling promiscuity, the full signaling landscape remains incompletely characterized, which may help explain the limited efficacy and potential cancer risks associated with lorcaserin. Here, we provide a comprehensive analysis of 5-HT<sub>2C</sub> signaling, confirming and building upon previous findings that the receptor engages Gi/o/z and G12/13 proteins in addition to its primary Gq/11 pathway, and that it preferentially recruits β-arrestin2 over β-arrestin1. We also show that increased RNA editing of the receptor attenuates signaling across all G protein pathways, particularly for G12/13, while preserving β-arrestin recruitment. Profiling of both 5-HT<sub>2C</sub>-selective and psychedelic ligands reveals diverse signaling profiles, with serotonergic psychedelics such as LSD and psilocin exhibiting a striking Gq/11 bias due to minimal secondary G protein activation. Altogether, this work provides a foundation for incorporating a broader view of 5-HT<sub>2C</sub> signaling modalities into future investigations of 5-HT<sub>2C</sub> drug development efforts.
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