Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism.
Emma M. Bonniwell, Rana Alabdali, Joseph J. Hennessey, John L. McKee, Natalie G. Cavalco, Josie C. Lammers, Ethan J. Moore, Luca Franchini, Cesare Orlandi, John D. Mccorvy
ACS Chem Neurosci September 13, 2025 DOI: 10.1021/acschemneuro.5c00647 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Psychedelics Hallucinogens Entheogens Mind-altering drugs Psychedelic compounds Biased agonism Selective agonism Receptor modulation Pathway-specific activation Receptor fine-tuning Selective engagement Serotonin receptors 5-ht2c receptor 5-HT Receptors Brain receptors Neurotransmitter receptors Therapeutic potential Novel treatments Drug development Psychiatric treatments Mental health Precise therapeutic benefits |
| Citations | 3 |
| Key points | The serotonin 2C receptor engages Gi/o/z and G12/13 proteins in addition to its primary Gq/11 pathway, and psychedelic ligands such as LSD and psilocin exhibit a striking Gq/11 bias due to minimal secondary G protein activation. |
Abstract
The serotonin 2C receptor (5-HT 2C ) 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 2C may contribute to psychedelic-induced therapeutic effects. Despite earlier evidence of 5-HT 2C 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 2C 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 2C -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 2C signaling modalities into future investigations of 5-HT 2C drug development efforts.