The trace amine-associated receptor 1 (TAAR1) plays a key role in the signaling of the hallucinogen LSD and several antipsychotic drugs. This work presents the molecular structures of the TAAR1-Gs protein complex bound to LSD and to the partial agonist RO5263397, a drug candidate for schizophrenia and addiction. Through mutagenesis, functional studies, and molecular dynamics simulations, the authors describe a versatile binding pocket in TAAR1 that adapts to recognize different ligands, including in the ligand-free state. These results clarify cross-species recognition and partial activation of TAAR1, providing a structural basis for designing new antipsychotic medications.
Post-traumatic stress disorder affects 3-4% of people globally each year. In a rat model of PTSD induced by single prolonged stress, a single low dose of ketamine (10 mg/kg) prevented anxiety-like behaviors. Ketamine also reversed stress-induced changes in the hippocampus: it increased expression of glucocorticoid receptor, brain-derived neurotrophic factor, phosphorylated GSK-3β, FKBP5, and CRH, while decreasing GSK-3β protein expression, and it improved synaptic structure. A GSK-3β inhibitor produced similar behavioral effects, suggesting ketamine works by regulating GSK-3β/GR signaling to improve synaptic plasticity.