Hallucinogens induce a specific barcode of phosphorylation on the serotonin2A receptor that underlies a weaker receptor desensitization and internalization

The serotonin (5-Hydroxytryptamine, 5-HT) 2A receptor represents one of the most striking examples where functional selectivity (or ligand-biased signaling) is transduced in distinct behaviours. This receptor is the primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline and psilocybin, which reproduce some of the core symptoms of schizophrenia and are often used to probe the disease. Why only some 5-HT2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and agonist activity (e.g. lisuride and ergotamine) lack such a psychoactive activity remains an incompletely resolved paradox. In a recent paper published in Molecular and Cellular Proteomics (doi: 10.1074/mcp.M113.036558) we demonstrated a biased phosphorylation of the 5-HT2A receptor in response to hallucinogenic versus non-hallucinogenic agonists that leads to a weaker receptor desensitization and internalization by hallucinogens.