Biased signaling via serotonin 5-HT2A receptor: From structural aspects to in vitro and in vivo pharmacology.
Acta pharmaceutica Sinica. B September 1, 2025 Michał K Jastrzębski, Piotr Wójcik, Angelika Grudzińska et al.
G protein-coupled receptors (GPCRs) are targets for many drugs, and recent work has revealed biased signaling, where a receptor selectively activates certain intracellular pathways (G proteins or β-arrestins). The serotonin 5-HT2A receptor is of particular interest because biased agonism might produce therapeutic benefits for depression and anxiety without causing hallucinations. This review covers methods for measuring biased signaling, from traditional binding assays to biosensors, and structural studies identifying key receptor residues. Novel biased ligands that activate only some pathways offer a path to antidepressant therapies without psychedelic effects. The 5-HT2A receptor also plays roles in memory and stress regulation. Understanding biased signaling could lead to safer GPCR-targeted psychiatric treatments.