It is unclear how the binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of the tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates cholesterol’s synaptic effects.
We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating its synaptic localization and activation by BDNF.
Extensive computational approaches, including atomistic molecular dynamics simulations, revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the standard mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.
Keywords: BDNF; antidepressant; cholesterol; fluoxetine; ketamine; molecular dynamic simulation; neurotrophin; plasticity.
Casarotto PC, Girych M, et, al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021 Mar 4;184(5):1299-1313.e19.