GABA Receptors

Question 1

What are some basic facts about GABA?

Answer 1

• A third of all synapses in the brain are GABAergic.
• GABA released from the presynaptic nerve endings inhibit action potential firing via phasic inhibition and control the activity of neurons via tonic inhibition.
• GABA is the main inhibitory NT in the CNS.

Question 2

How is GABA signalled?

Answer 2

• GABA is synthesised from glutamate by the enzyme glutamic acid decarboxylase (GAD)
• It is packaged into vesicles by the vesicular GABA transporter (vGAT) where it is released via exocytosis.
• Released GABA is taken up into neurones and glia by the GABA transporter (GAT).
• GABA uptake is a sodium and chloride dependent process.

Question 3

What are the two classes of GABA receptors?

Answer 3

1. GABA-A receptors: ionotropic (fast inhibitory signals) and are found in the post-synaptic region.
2. GABA-B receptors: metabotropic (slow inhibitory modulation) and are found both post and presynaptically.

Question 4

GABA-A receptors.

Answer 4

• Belong to the cys-loop family where it consists of 5 subunits which cross the membrane 4 times. There is also a large intracellular loop domain between the TM3 and TM4.
• The GABA binding site between the alpha and beta subunits while the benzodiazepine (negative allosteric modulator whose presence is increased during hyperpolarisation) binding site is between the gamma and alpha subunits.
• GABA is the endogenous molecule that activates GABA-A (binding in extracellular domain).
• BZ also binds in the extracellular domain while Etomidate (an anaesthetic that acts as a positive allosteric modulator binds in the membrane spanning domain.
• Synaptic receptors have a lower affinity and faster desensitisation that extra synaptic receptors. This is because of the delta subunit present in extra synaptic.

Question 5

GABA-B receptors

Answer 5

• GPCR type receptors which are heterodimers, subunit B1 binds GABA while B2 binds the G-protein.
• GABA-B receptors give slowed sustained signalling that has a predominately inhibitory (hyperpolarising) effect.
• GABA binding causes an allosteric change that activates Gi/o domain. stimulates the phosphorylation of GDP to GTP which serves to dissociate the G protein upon GTP binding.
• bY subunit interacts with ion channel which inhibits Ca2+ channel while activating K+ stimulating hyperpolarisation.