GABA, GABA, GABA, what does it actually do in the brain?

Indigophoton · May 16, 2018

This might be of background interest to some.

Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is the control knob of all control knobs. But why GABA? What, if anything, might be so special about the molecule?

To look at it, there is nothing inherently peculiar about the small four-carbon backbone structure of GABA. Solvation effects in solution allow GABA to take on five different possible conformations, some compact, and others more extended. At the receptor level, this flexibility means that GABA is a highly 'druggable' target. In other words, pharmaceutical analogs of GABA are more rigidly pocketable in select receptor subsets, and therefore potentially very specific.

If GABA itself is completely ordinary, does it, perhaps by chance, sit in some prized location within metabolism? Some of the apex positions in metabolic cycles are occupied by molecules like Acetyl-CoA and ATP. Acetyl-CoA sits right at the intersection of glycolysis, the TCA cycle, ketone production, β-oxidation of lipids, and fatty acid elongation. It even plugs directly into synthesis of the neurotransmitter acetylcholine. Curiously, there are no major receptor systems associated with this complex molecule that might otherwise keynote its position inside the cell.

ATP has a more condensed footprint than Acetyl-CoA, but it is certainly no slouch. It directly links oxidative phosphorylation with nucleotide metabolism, and is piloted by its own special set of membrane receptors. Like the GABA ecosystem, ATP comes with the full-service suite containing all the expected ionotropic and metabotropic receptor functions. In the case of GABA, these receptor effects have traditionally been neatly grouped into GABAA receptors, which act as channels for chloride ions, and GABAB receptors, which signal through G-protein bound to their undercarriage.

This tidy picture was recently shaken up with reports of GABA directly gating potassium (K) channels. K channels respond to voltage and normally act to hyperpolarize a neuron, or repolarize a it after a spike. The authors of a paper just published in Nature found that the KCNQ receptor family has an evolutionarily conserved spot set aside just for GABA. When GABA is present there, the voltage set point of these channels is shifted to a more polarized state.

KCNQ channels carry the so-called 'M' current, which can be triggered by the agonist muscarine. Because of this receptor-like action, lack of inactivation, and voltage range of operation, these M channels are said to be regulators of neuronal excitability.
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GABA-glutamate-glutamine cycle at cortical synapses. Credit:studyblue.com

The GABA shunt. Credit: frontiers.org
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https://medicalxpress.com/news/2018-05-gaba-brain.amp

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GABA, GABA, GABA, what does it actually do in the brain?

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