3 GABAergic system

From: <a href="http://fblt.cz/en/skripta/regulacni-mechanismy-2-nervova-regulace/5-neurotransmisni-systemy/">4. Neurotransmitter Systems • Functions of Cells and Human Body</a>

GABAergic system

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Similar to glutamate its distribution is diffuse and a distinct neurotransmitter system cannot be identified.

Synthesis and inactivation of GABA – cycle neuron-astrocyte

Most GABA is synthesised by the decarboxylation of glutamate catalysed by glutamate decarboxylase. As with glutamate, the precursor is glutamine transported from astrocytes. Glutamine is converted inside a neuron to glutamate (catalysed by glutaminase), which is then decarboxylated to GABA.

Once released into the synaptic cleft GABA is mainly taken up by astrocytes and converted back to glutamine. The gamma-amino group of GABA is first transaminated to give an aldehyde group thus forming succinate semialdehyde. This reaction is catalysed by GABA transaminase. Succinate semialdehyde is then oxidised to succinate, which enters the TCA cycle. A half-turn of the cycle takes us to 2-oxoglutarate, which can be (trans)aminated to glutamate and further amidated to glutamine using ammonia and ATP. Glutamine is then exported and the cycle closes.

There are three subtypes of GABAergic receptors:

1) GABAA

This is an ionotropic receptor allowing the permeation of chloride anions. Its opening generally leads to an influx of chloride into the cytoplasms and hence to a lowering of the membrane potential.

It forms a supramolecular receptor complex, which in addition to GABA binds benzodiazepines, barbiturates, corticosteroids and alcohol. All these binding sites affect the opening of the central pore and all act to inhibit the neuron either directly via opening the pore or indirectly by potentiating the binding of GABA.

2) GABAB

This is a metabotropic receptor couple to a Gi protein inhibiting adenylate cyclase. The resulting decrease in cAMP levels changes membrane protein phosphorylation status, which leads to an increase in potassium permeability (membrane hyperpolarisation) and a decreased activity of calcium channels. The result is a decreased amount of neurotransmitter released by the neuron.

This receptor is found in abundance in many areas of the cortex, thalamus and cerebellum.

3) GABAC (recently renamed to GABAA-rho receptor)

This is an ionotropic receptor connected to a chloride channel. In contrast to GABAA receptors they open more slowly and remain open for a longer period of time.