Quantitative Phosphoproteomics Unravels Biased Phosphorylation of Serotonin 2A Receptor at Ser280 by Hallucinogenic versus Nonhallucinogenic Agonists
Molecular & Cellular Proteomics March 18, 2014 Samah Karaki, Carine Bécamel, Samy Murat et al. 73 citations
The serotonin 5-HT(2A) receptor is a primary target of psychedelic hallucinogens like LSD, mescaline, and psilocybin, which mimic some schizophrenia symptoms. A paradox is that some 5-HT(2A) receptor agonists cause hallucinations while structurally similar ones do not. Comparing the phosphoproteome in HEK-293 cells expressing the 5-HT(2A) receptor, 16 phosphorylation sites differed between the hallucinogen DOI and the nonhallucinogenic agonist lisuride. One site, serine 280 in the receptor's third intracellular loop, was specifically phosphorylated by hallucinogens. In mice, DOI enhanced this phosphorylation in the prefrontal cortex, while lisuride did not. Hallucinogens caused less receptor desensitization than nonhallucinogenic agonists. Mutating serine 280 altered desensitization, revealing biased phosphorylation underlies different desensitization capacities.