Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism.
ACS Chem Neurosci September 13, 2025 Emma M. Bonniwell, Rana Alabdali, Joseph J. Hennessey et al. 3 citations
The serotonin 2C receptor (5-HT 2C ) is involved in processes like mood and appetite and is a target for drugs treating obesity, addiction, and depression, including psychedelics. This analysis of 5-HT 2C signaling confirms that the receptor activates multiple G protein pathways—Gi/o/z and G12/13 in addition to its main Gq/11 pathway—and preferentially recruits β-arrestin2 over β-arrestin1. Increased RNA editing of the receptor reduces signaling across all G protein pathways, especially G12/13, while preserving β-arrestin recruitment. Profiling of ligands shows that psychedelics like LSD and psilocin produce a strong Gq/11 bias by minimally activating other G proteins. These findings provide a foundation for considering broader signaling modalities in 5-HT 2C drug development.