Summary: SSRI’s, ketamine, and tricyclic antidepressants all bind with TrkB. The findings challenge the roles serotonin and glutamate receptors play in the effects of antidepressant medications.
Source: University of Helsinki
The effects of selective serotonin reuptake inhibitors (SSRIs) and other conventional antidepressants are believed to be based on their increasing the levels of serotonin and noradrenalin in synapses, while ketamine, a new rapid-acting antidepressant, is thought to function by inhibiting receptors for the neurotransmitter glutamate.
Neurotrophic factors regulate the development and plasticity of the nervous system. While all antidepressants increase the quantity and signalling of brain-derived neurotrophic factor (BDNF) in the brain, the drugs have so far been thought to act on BDNF indirectly, through serotonin or glutamate receptors.
A new study published this week in Cell demonstrates, however, that antidepressants bind directly to a BDNF receptor known as TrkB. This finding challenges the primary role of serotonin or glutamate receptors in the effects of antidepressants.
The international study, which was collaboratively led by the Neuroscience Center and the Department of Physics at the University of Helsinki, investigated the binding of antidepressants from different drug classes to the TrkB receptor. All the antidepressants examined, including fluoxetine (an SSRI), imipramine (a tricyclic antidepressant) and the rapid-acting ketamine interacted with TrkB.
“We found that all antidepressants boost BDNF signalling by binding to its TrkB receptor. This signalling is necessary for the cellular and behavioural effects of antidepressants in our experimental models. The effects of antidepressant on plasticity do not therefore require increases in the serotonin levels or the inhibition of glutamate receptors, as previously thought,” says Professor Eero Castrén, the principal investigator of the study.
Molecular modelling helped to locate the binding site of antidepressants
The binding site of antidepressants in the transmembrane region of TrkB was identified through molecular modelling, performed in Professor Ilpo Vattulainen’s research group at the Department of Physics, University of Helsinki. Biochemical binding studies and mutations introduced in the TrkB receptor verified the site.
Molecular modelling also demonstrated that the structure of TrkB is sensitive to the cholesterol concentration of the cell membrane. TrkB is displaced in cholesterol-rich membrane compartments, such as synaptic membranes.
“The drug binding stabilises dimers, structures composed of two TrkB receptors, inhibiting the displacement of the TrkB receptors and increasing their quantity in synaptic cell membranes, which boosts the effects of BDNF. That is to say that the drugs do not directly activate TrkB. Instead, they sensitise the receptor to the effects of BDNF,” Castrén explains.
In addition to findings pertaining to the effects of antidepressants, the study produced a substantial amount of new information on the structure and function of the growth factor receptor.
Why does ketamine have such a rapid effect?
Ketamine, which has been used as an anaesthetic, is becoming increasingly utilized as an antidepressant. The researchers were surprised to find that both slow-acting SSRIs and rapid-acting ketamine act by binding to the same site in TrkB.
SSRI drugs bind to the serotonin transporter protein much more avidly than to TrkB, but the binding of ketamine to the glutamate receptor and TrkB occurs at similar drug concentrations.
“Previous studies have shown that in SSRI therapy, drugs gradually reach the high brain concentration needed for binding to the TrkB receptor, whereas intravenously administered ketamine and esketamine as a nasal spray reach the level needed for binding quickly, in a matter of minutes. The difference in the onset of action for SSRIs and ketamine may be caused by their different capacity to reach in the brain the concentration needed for binding with TrkB receptors,” Castrén says.
About this neuropsychopharmacology research news
Source: University of Helsinki Contact: Eero Castrén – University of Helsinki Image: The image is in the public domain
Antidepressant drugs act by directly binding to TRKB neurotrophin receptors
•Several antidepressants, including SSRIs and ketamine, directly bind to TRKB
•TRKB dimerization at transmembrane region forms a binding pocket for fluoxetine
•Antidepressant binding to TRKB facilitates BDNF action and plasticity
•Point mutation in TRKB transmembrane region blocks the effects of antidepressants
It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect.
We discovered that the transmembrane domain of 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 synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its 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 common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.