Faculty Collaboration Database

Serotonin 5-HT_2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism. ACS Chem Neurosci 2025 Oct 01;16(19):3899-3914

Date

09/13/2025

Pubmed ID

40944639

Pubmed Central ID

PMC12629614

DOI

10.1021/acschemneuro.5c00647

Scopus ID

2-s2.0-105017796655 (requires institutional sign-in at Scopus site)   4 Citations

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.

Author List

Bonniwell EM, Alabdali R, Hennessey JJ, McKee JL, Cavalco NG, Lammers JC, Moore EJ, Franchini L, Orlandi C, McCorvy JD

Authors

Emma M. Bonniwell Postdoctoral Researcher in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
HEK293 Cells
Hallucinogens
Humans
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
Signal Transduction
beta-Arrestin 2