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Written | Qi depression is the most common depressive disorder, with significant and lasting depression as the main clinical feature.
In severe cases, people with severe illness can have pessimistic moods and even suicide attempts or behaviors.
Antidepressant (antidepressant, AD) refers to a group of psychotropic drugs mainly used to treat mental illness with emotional depression as the prominent symptom.
The difference from stimulants is that they can only eliminate the depressive symptoms of depressed patients, but cannot make them normal.
People's mood improves.
Up to now, several targets for ADs have been confirmed, but it is not clear how the combination with these targets translates into clinical effects.
Basically all ADs, including KET and R, R-HNK, increase brain-derived neurotrophic factor (BDNF) through neurotrophic tyrosine kinase receptor 2 (TRKB) Expression and signal transduction [1].
In addition, studies have shown that TRKB signaling is bidirectionally related to brain cholesterol (cholesterol, CHOL) metabolism.
On the one hand, BDNF can promote the production of CHOL in neurons, and in turn, CHOL can also regulate TRKB signaling [2, 3].
These research data prompted people to speculate that the potential interaction between TRKB, CHOL and ADs may explain the mechanism of action of antidepressants.
Recently, the Eero Castrén team from the University of Helsinki in Finland published an article in the Cell magazine titled Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
This study proposes typical and fast-acting antidepressants and BDNF receptors.
The direct combination of TRKB can explain the cellular biology and behavioral effects of antidepressants.
This mechanism directly connects the effects of antidepressants with neuroplasticity, which helps to understand why typical antidepressants have slow effects and how to treat antidepressants.
The molecular effects of depression drugs translate into emotional recovery in clinical patients.
It is well known that CHOL can promote neuronal maturation and plasticity, but how it exerts these effects is unclear.
CHOL is thought to interact with proteins through the CRAC domain [4].
The author of this study also just discovered a CRAC motif in the transmembrane domain (TMD) of TRKB, suggesting that CHOL may directly interact with TRKB.
Under normal circumstances, TRKB mainly exists in intracellular vesicles that BDNF cannot enter.
The authors found that CHOL treatment can increase TRKB cells indicating translocation, and the key residue Y433 in the CRAC motif plays an important role in this translocation process.
, Thereby promoting BNDF signal transduction.
The author also further verified the interaction mode of CHOL and TRKB through all-atom molecular dynamics simulation (MD).
It is now known that almost all ADs can promote TRKB signaling in rodents, and these ADs can interact with phospholipids and accumulate in lipid rafts [5].
The authors found that CHOL not only does not compete with ADs such as FLX or R, R-HNK for the binding site of TRKB, but also increases the binding ability of these drugs with TRKB, suggesting that CHOL and ADs have two different cooperative recognition mechanisms.
Next, the author performed an MD simulation, and the results showed that there is a binding site in the fissure outside the cell of the FLX and TRKB-TMD dimer, and FLX preferentially plays a role at high CHOL concentrations.
When the drug is discharged, the dimer will Transform into a more parallel conformation (see Figure 1).
Figure 1.
Model of interaction between FLX and TRKB transmembrane domain.
Based on the above results, the author wants to know whether ADs can promote TRKB membrane transport.
To this end, the author used the fluorescence recovery (FRAP) experiment after photobleaching of primary hippocampal neurons (DIV14) to evaluate the mobility of TRKB in neurons.
The results showed that in neurons pretreated with BDNF, FLX and KET, TRKB was Cell surface migration increased, and this effect was disrupted in neurons containing TRKB Y433F mutant.
In addition, we know that BDNF is a key mediator of neuronal synaptic plasticity and is necessary for long-term potentiation (LTP), and these effects are mediated by TRKB [6].
It should be noted that pulse stimulation of brain slices from heterozygous mice carrying the TRKB Y433F mutation failed to induce any significant enhancement.
Furthermore, does the interaction between ADs and TRKB affect neuronal plasticity-dependent learning and behavior? The authors found that administration of FLX for seven consecutive days can promote long-term memory in rats, and both FLX and KET administration can significantly reduce the immobility of wild-type mice in the forced swimming test and promote the elimination of conditioned fear memory.
Both are ineffective in TRKB Y433F mice.
In addition, the authors also observed that when ADs were combined with pravastatin, many of the above-mentioned behavioral effects disappeared, suggesting that the behavioral effects of BDNF on TRKB signaling depend on CHOL induction.
In general, before this, although BDNF signaling was known to be essential to the action of almost all antidepressants, this importance was thought to be indirectly mediated by other proteins, such as 5HTT and NMDA receptors.
. This study shows that antidepressants can directly bind to TRKB and allosteric to increase BDNF signaling, thereby directly linking the effects of antidepressants with neuronal plasticity, and solving the basic molecular mechanism of the clinical efficacy of antidepressants.
.
Original link: https://doi.
org/10.
1016/j.
cell.
2021.
01.
034 Platemaker: Eleven References 1.
Autry, AE, and Monteggia, LM (2012).
Brain-derived neurotrophic factor and neuropsychiatric disorders.
Pharmacol.
Rev.
64, 238–258.
2.
Suzuki, S.
, Kiyosue, K.
, Hazama, S.
, Ogura, A.
, Kashihara, M.
, Hara, T.
, Koshimizu, H.
, and Kojima, M.
(2007).
Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development.
J.
Neurosci.
27, 6417–6427.
3.
Pereira, DB, and Chao, MV (2007).
The tyrosine kinase Fyn determines the localization of TrkB receptors in lipid rafts.
J.
Neurosci.
27, 4859–4869.
4.
Fantini, J.
, Epand, RM, and Barrantes, FJ (2019).
Cholesterol-Recognition Motifs in Membrane Proteins.
Adv.
Exp.
Med.
Biol.
1135, 3–25.
5 .
Chen, J.
, Korostyshevsky, D.
, Lee, S.
, and Perlstein, EO (2012).
Accumulation of an antidepressant in vesiculogenic membranes of yeast cells triggers autophagy.
PLoS ONE 7, e34024.
6.
Ernfors, P.
, and Bramham, CR (2003).
The coupling of a trkB tyrosine residue to LTP.
Trends Neurosci.
26, 171 –173.
Reprinting instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt. BioArt reserves all statutory rights and offenders must be investigated.
In severe cases, people with severe illness can have pessimistic moods and even suicide attempts or behaviors.
Antidepressant (antidepressant, AD) refers to a group of psychotropic drugs mainly used to treat mental illness with emotional depression as the prominent symptom.
The difference from stimulants is that they can only eliminate the depressive symptoms of depressed patients, but cannot make them normal.
People's mood improves.
Up to now, several targets for ADs have been confirmed, but it is not clear how the combination with these targets translates into clinical effects.
Basically all ADs, including KET and R, R-HNK, increase brain-derived neurotrophic factor (BDNF) through neurotrophic tyrosine kinase receptor 2 (TRKB) Expression and signal transduction [1].
In addition, studies have shown that TRKB signaling is bidirectionally related to brain cholesterol (cholesterol, CHOL) metabolism.
On the one hand, BDNF can promote the production of CHOL in neurons, and in turn, CHOL can also regulate TRKB signaling [2, 3].
These research data prompted people to speculate that the potential interaction between TRKB, CHOL and ADs may explain the mechanism of action of antidepressants.
Recently, the Eero Castrén team from the University of Helsinki in Finland published an article in the Cell magazine titled Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
This study proposes typical and fast-acting antidepressants and BDNF receptors.
The direct combination of TRKB can explain the cellular biology and behavioral effects of antidepressants.
This mechanism directly connects the effects of antidepressants with neuroplasticity, which helps to understand why typical antidepressants have slow effects and how to treat antidepressants.
The molecular effects of depression drugs translate into emotional recovery in clinical patients.
It is well known that CHOL can promote neuronal maturation and plasticity, but how it exerts these effects is unclear.
CHOL is thought to interact with proteins through the CRAC domain [4].
The author of this study also just discovered a CRAC motif in the transmembrane domain (TMD) of TRKB, suggesting that CHOL may directly interact with TRKB.
Under normal circumstances, TRKB mainly exists in intracellular vesicles that BDNF cannot enter.
The authors found that CHOL treatment can increase TRKB cells indicating translocation, and the key residue Y433 in the CRAC motif plays an important role in this translocation process.
, Thereby promoting BNDF signal transduction.
The author also further verified the interaction mode of CHOL and TRKB through all-atom molecular dynamics simulation (MD).
It is now known that almost all ADs can promote TRKB signaling in rodents, and these ADs can interact with phospholipids and accumulate in lipid rafts [5].
The authors found that CHOL not only does not compete with ADs such as FLX or R, R-HNK for the binding site of TRKB, but also increases the binding ability of these drugs with TRKB, suggesting that CHOL and ADs have two different cooperative recognition mechanisms.
Next, the author performed an MD simulation, and the results showed that there is a binding site in the fissure outside the cell of the FLX and TRKB-TMD dimer, and FLX preferentially plays a role at high CHOL concentrations.
When the drug is discharged, the dimer will Transform into a more parallel conformation (see Figure 1).
Figure 1.
Model of interaction between FLX and TRKB transmembrane domain.
Based on the above results, the author wants to know whether ADs can promote TRKB membrane transport.
To this end, the author used the fluorescence recovery (FRAP) experiment after photobleaching of primary hippocampal neurons (DIV14) to evaluate the mobility of TRKB in neurons.
The results showed that in neurons pretreated with BDNF, FLX and KET, TRKB was Cell surface migration increased, and this effect was disrupted in neurons containing TRKB Y433F mutant.
In addition, we know that BDNF is a key mediator of neuronal synaptic plasticity and is necessary for long-term potentiation (LTP), and these effects are mediated by TRKB [6].
It should be noted that pulse stimulation of brain slices from heterozygous mice carrying the TRKB Y433F mutation failed to induce any significant enhancement.
Furthermore, does the interaction between ADs and TRKB affect neuronal plasticity-dependent learning and behavior? The authors found that administration of FLX for seven consecutive days can promote long-term memory in rats, and both FLX and KET administration can significantly reduce the immobility of wild-type mice in the forced swimming test and promote the elimination of conditioned fear memory.
Both are ineffective in TRKB Y433F mice.
In addition, the authors also observed that when ADs were combined with pravastatin, many of the above-mentioned behavioral effects disappeared, suggesting that the behavioral effects of BDNF on TRKB signaling depend on CHOL induction.
In general, before this, although BDNF signaling was known to be essential to the action of almost all antidepressants, this importance was thought to be indirectly mediated by other proteins, such as 5HTT and NMDA receptors.
. This study shows that antidepressants can directly bind to TRKB and allosteric to increase BDNF signaling, thereby directly linking the effects of antidepressants with neuronal plasticity, and solving the basic molecular mechanism of the clinical efficacy of antidepressants.
.
Original link: https://doi.
org/10.
1016/j.
cell.
2021.
01.
034 Platemaker: Eleven References 1.
Autry, AE, and Monteggia, LM (2012).
Brain-derived neurotrophic factor and neuropsychiatric disorders.
Pharmacol.
Rev.
64, 238–258.
2.
Suzuki, S.
, Kiyosue, K.
, Hazama, S.
, Ogura, A.
, Kashihara, M.
, Hara, T.
, Koshimizu, H.
, and Kojima, M.
(2007).
Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development.
J.
Neurosci.
27, 6417–6427.
3.
Pereira, DB, and Chao, MV (2007).
The tyrosine kinase Fyn determines the localization of TrkB receptors in lipid rafts.
J.
Neurosci.
27, 4859–4869.
4.
Fantini, J.
, Epand, RM, and Barrantes, FJ (2019).
Cholesterol-Recognition Motifs in Membrane Proteins.
Adv.
Exp.
Med.
Biol.
1135, 3–25.
5 .
Chen, J.
, Korostyshevsky, D.
, Lee, S.
, and Perlstein, EO (2012).
Accumulation of an antidepressant in vesiculogenic membranes of yeast cells triggers autophagy.
PLoS ONE 7, e34024.
6.
Ernfors, P.
, and Bramham, CR (2003).
The coupling of a trkB tyrosine residue to LTP.
Trends Neurosci.
26, 171 –173.
Reprinting instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt. BioArt reserves all statutory rights and offenders must be investigated.
