GABA and GABA receptors

Descirbe GABA.

- Main inhibitory neurotransmitter in the brain.

- 20% of CNS neurones use GABA.

- Mostly short interneurones use GABA.

- Used widely in the brain.

Describe GABA synthesis

- Precrusor is glucose.

- Formed from glutamate using GAD.

- GABA shunt preserves GABA

What is the GABA shunt and explain the process.

- The metabolism of GABA

- GABA-T converts GABA into succinic semialdehyde (SSA).

- Succinic semialdehyde dehydrogenase then oxidizes SSA into succinate.

- Succinate enters the TCA cycle to reform glutamate.

Describe the release of GABA from the pre-synaptic neurone.

- GABA is synthesised from glutamate and is packaged into vesicles.

- It is then released via exocytosis into the synapse.

How can GABA be recycled?

- GABA can be reuptaken back into neurone via GAT.

- This allows repackaging into vesicles to be used again.

- Can also be taken up by GAT3 on astrocytes.

What drug increases GABA activity?

- Vigabatrine

- Guvacine

- Tiagabine

How does vigabatrine increase GABA activity?

- Vigabatrin

Irreversibly inhibits GABA-T, preventing GABA degradation.

- This Increases GABA concentration in the synapse, enhancing inhibitory neurotransmission.

How does Guvacine and Tiagabine increase GABA activity?

Both work by inhibiting the GABA transporter (GAT-1), preventing GABA reuptake and increasing its synaptic concentration.

What receptors does GABA act on?

- GABAa

- GABAb

Describe the structure of GABAa receptors.

- 5 out of 19 different subunits make them up (pentameric)

- Contains extracellular N-terminus, 4 transmembrane domains, short extracellular C-terminus, Long intraceullular loop between TM3 and TM4, TM2 lines the ion channel

Describe GABAa receptors.

- Post-synaptic Ionotropic receptors.

- Only Cl- ions can pass through after GABA binding.

What does GABA binding to GABAa receptors cause?

- Causes hyperpolarisation of post-synaptic neurone as it causes Cl- to move in causing it to become more negative.

- This reduces excitability as it becomes harder to depolarise.

What binding sites can drugs exploit on GABAa receptors?

- Receptor site (where GABA binds)

- Benzodiazepine site

- Barbiturate site

- Steroid site

- Channel blocking site

Describe the GABA site on GABAa receptors.

- Located between a and b subunit interface.

- There are 2 sites per pentamer.

- (agonist) Muscimol can bind to this site.

- (antagonist) Biculline can bind to this site.

- GABA binding leads to opening of the Cl- channel.

Describe the benzodiazepine site on GABAa receptors.

- Enhance the effects of GABA (positive allosteric modulators).

- Causes an increase in affinity for GABA.

- Increases amount of time channel is open for, increasing response from GABA binding.

- E.g., diazepam

Describe the barbiturates site of GABAa receptors.

- Drugs binding to this site enhance the effects of GABA upon binding.

- Increases amount of time channel is open for, increasing response from GABA binding.

- E.g., pentobarbitol

Describe the steroid site on GABAa receptors.

- Enhance the effects of GABA.

- Act on transmembrane regions of α subunit (M1 and M2).

- E.g., progesterone

Describe the channel blocking site on GABAa receptors.

- Inside the channel pore.

- Picrotoxin binds here to reduce GABA activity via reducing Cl- influx.

- Channel needs to be open already to gain access to this site.

Describe the structure of GABAb receptors.

- Metabotropic

- GPCRs through Gai/o subunit.

- Form dimers with GABAb1 and GABAb2

Describe the action of GABAb receptors.

- Signal inhibits CaV channels and reduces neurotransmitter release from presynaptic terminals.

- Opens K+ channels to increase hyperpolarisation

Describe glycine.

- An inhibitory neurotransmitter.

- Also a co-agonist at NMDA receptors.

- Glycine transporters can remove glycine from extracellular fluid.

Describe the glycine receptor.

- Ligand gated Cl- channel.

- 5 glycine receptor subunits cloned.

- Blocking of this receptor causes convulsion as prevents inhibitory effect of glycine.