GABA, gamma amino butyric acid, inhibitory neurotransmitter
Metabolism
GABA, NH2 - CH2 - CH2 - CH2-COOH, is present in neurons where it is synthesized from glutamic acid,
by the catalytic action of glutamic acid decarboxylase (GAD) with pyridoxal phosphate as cofactor. Stored
in granules of presynaptic terminations and released into the synaptic cleft, it activates specific postsynaptic
receptors GABA-A and GABA-B. Part of GABA released is reuptaken by presynaptic terminations (neuronal reuptake),
another part diffuses and is partly taken up by glial cells (glial uptake) .Mitochondrias of glial cells transform
GABA, under the influence of GABA transaminase, with pyridoxal as cofactor, into succinic acid semi-aldehyde,
itself transformed into succinic acid. GABA transaminase activity could be excessive in certain epileptic patients.
Metabolism of GABA
Receptors and effects
GABA exerts its effects via two types of receptors: GABA-A and GABA-B receptors
GABA-A receptors
The GABA-A receptor, is an ion channel receptor i e an ionotropic receptor. It consists of a macromolecular complex which, in addition to binding sites for GABA, involves binding sites for benzodiazepines, barbiturates, certain steroids. In an open state this receptor-channel is permeable preferentially to Cl ions and incidentally to Br ions.
The opening of this permeable receptor-channel is activated directly by GABA which is the essential transmitter: The binding of two molecules of GABA induces its opening, penetration of Cl - ions and cellular hyperpolarisation. However, an excess of GABA desensitizes the receptors.
GABA-A receptor
A characteristic of GABA-A receptor is to be allosterically modulated by other receptors which enhance or reduce GABA effect. These receptors are located near the binding sites of GABA. They are receptors to benzodiazepines, barbiturates and certain steroids like allopregnanolone, metabolite of progesterone, and tetrahydrodeoxycorticosterone. These compounds enhance GABA effects, but are without effect in absence of GABA.
There are agonists activating receptors which induce the opposite effects to those of benzodiazepines and which are called inverse agonists.
In the nervous system, increase in frequency of opening of the chloride receptor-channel, allowing entry of chloride is at the origin of inhibiting effects, and its decrease, at origin of opposite effects. The consequences of this modulation of influx of chloride are summarized in the following table.
Opening :
Chloride influx |
Closing :
Inhibition of chloride- influx |
| Anxiolytic effect |
Anxiogenic effect |
| Hypnotic sedative |
Stimulant |
| Anticonvulsive |
Proconvulsive |
| Amnestic effect |
Promnestic effect ? |
| Muscular relaxation |
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Effects of modulation of opening of receptor-channel GABA-A
The drugs with the same type of effect on chloride channel share common pharmacological properties, but not necessarily identical. The differences observed between molecules come from their pharmacokinetic features: rate of transfer into the brain, duration of action, and pharmacodynamic: predominant effect on limbic or cortical structures for example.
It should be stressed that for the majority of molecules their effects were described prior to understanding their mechanism of action.
GABA-B receptors
There are two types of GABA-B receptors, GABA-B R1 and GABA-B R2, present in the form of dimers and coupled to G proteins. They are presynaptic and postsynaptic.
Activation of presynaptic GABA-B receptors decreases the release of GABA and of different transmitters.
Activation of postsynaptic GABA-B receptors modulates the opening of potassium channels, which induces an intracellular potassium exit and consequently a membrane hyperpolarisation. Their role in physiology and pathology is rather poorly known but their stimulation induces a relaxation of skeletal muscles by inhibition of monosynaptic and polysynaptic reflex transmission in the spinal cord.
Stimulation of GABA-B receptors present in bronchi reduces bronchoconstriction, perhaps by inhibiting release of acetylcholine and tachykinins as substance P. It could also have an antitussive effect.
Note:
Receptors of GABA-C type were described. One can regard them as a subclass of GABA-A receptors, i.e. receptor-channels allowing chloride enter when they are activated. They were described primarily in hippocampus and retina.
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