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Got on the stage? Academician Wang Yutian revealed that excitatory transmitters directly bind to inhibitory receptors to enhance inhibitory currents

 Last Update: 2022-10-20
 Source: Internet
 Author: User

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In the mammalian brain, the excitability of synapses is mainly maintained by glutamate by binding to ionic glutamate receptors, while the inhibitory properties of synapses are mainly mediated
by γ-aminobutyric acid (GABA) by binding ionic GABAA receptors.
Maintaining synaptic excitation and inhibition of balance is essential
for the normal physiological function of the brain.
When there is an imbalance in excitation inhibition, it can lead to the occurrence of
mental diseases such as Alzheimer's disease, schizophrenia, autism and epilepsy.

The mutual regulation between excitability and inhibition can occur at the
neural circuit, cellular, and molecular levels.
At the neural circuit level, neurons affect the activity of excitatory or inhibitory neurons through remote projection, or enhance or inhibit the excitatory input
of neurons through feedforward inhibition.

At the cellular level, the excitatory synapses and inhibitory synapses of neurons work together to determine whether the cell is excited or inhibited
.
At the molecular level, glutamate regulates excitatory and inhibitory currents
through glutamate receptors or GABA receptors.
But it remains unclear
whether excitatory neurotransmitters can bind to GABAA receptors.

On October 3, 2022, Yutian Wang's team from the Brain Research Center of the Department of Medicine at the University of British Columbia, Canada, published a paper entitled "Glutamate and GABAA receptor crosstalk mediates homeostatic regulation" in the journal Signal transduction and targeted therapy of neuronal excitation in the mammalian brain", found that the excitatory neurotransmitter glutamate can directly bind to GABAA receptors, increasing GABAA receptor-mediated synaptic currents
.

Glutamate and its structural analogues enhance GABAA receptor-mediated synaptic currents

To investigate whether glutamate could affect the function of GABAA receptors, the researchers transferred two different classes of GABAA receptors in the 293T cell line: α1β2 and α1β2γ2
.
Patch-clamp recordings found that the combined application of glutamate and GABA can greatly increase the amplitude of GABA current, and this current can be completely blocked by the GABAA receptor antagonist poached peonyine, indicating that the induced current is a pure GABA current
.
The glutamate structural analogues AMPA and KA significantly enhance the GABA current mediated by α1β2 GABAA receptors
.

Figure 1: Glutamate and its structural analogues enhance GABAA receptor-mediated synaptic currents

Glutamic acid binds to amino acid residues at the GABAA receptor α+β-interface

The above results indicate the presence of glutamate binding sites on GABAA receptors, and since glutamate-enhanced GABA currents have little to do with the γ subunits of GABAA receptors, this glutamate binding site should be present on
α and β subunits.
The binding of GABA to GABAA receptors occurs at the β+α- interface, so the binding of glutamate is most likely to occur at the α+β- interface
.
The molecular docking model was used to look for the binding region of glutamate and GABAA receptors at the α+β-interface, and it was found that there were two glutamate binding regions
at the α+β-interface.

Figure 2: The binding region of glutamate at the GABAA receptor α+β-interface

The γ subunit of the GABAA receptor prevents the binding of glutamate by disrupting the α+β-interface structure

The previous step confirmed that the glutamate binding region is formed
by the α of the α+β-interface and key residues of the β subunit.
α1β2 GABAA receptor has two α+β- interfaces, while α1β2γ2 GABAA receptor only exists one α+β- interface, but glutamic acid cannot increase GABA current through γ subunits, so the presence of γ subunits may destroy the α+β- interface structure
.
Based on the above situation, the researchers designed the mutant γR197E of the γ subunit, and found that the GABAA receptor of α1β2γR197E can accommodate two glutamic acids and enhance the glutamate-mediated GABA current
.

Figure 3: The γ subunit of the GABAA receptor prevents the binding of glutamate by disrupting the α+β-interface structure

summary

In this study, we innovatively discovered glutamate enhances GABAA receptor-mediated GABA currents, and a new glutamate binding site is found in GABAA receptors, which only requires the α and β subunits of GABAA receptors, and based on this binding site, a broader spectrum of GABAA receptor positive modulators can be designed, which may be more effective in treating anxiety and epilepsy
.

【References】

1.
Wen, Y.
, Dong, Z.
, Liu, J.
et al.
Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain.
Sig Transduct Target Ther 7, 340 (2022).
https://doi.
org/10.
1038/s41392-022-01148-y

The images in the article are from references

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