GABA-ergic transmission

Question 1

What are the main inhibitory amino acid neurotransmitters in CNS?

Answer 1

GABA

Glycine

Question 2

What sort of amino acids are inhibitory ones?

Answer 2

Neutral

Question 3

What sort of amino acids are excitatory ones?

Answer 3

Acidic

Question 4

What are the main excitatory amino acids?

Answer 4

Glutamate
Aspartate
(L-homocysteine)

Question 5

Why is GABA given its name?

Answer 5

The amino group is on the gamma carbon and the carboxylic acid is on the alpha carbon

Question 6

Where are GABA neurones found?

Answer 6

Cerebral cortex
Cerebellum
Hippocampus
Corpus striatum
Hypothalamus
Dorsal horn of spinal cord

Question 7

How much GABA in in the PNS?

Answer 7

Relatively little

Question 8

What percentage of synapses respond to GABA?

Answer 8

Large proportion- 30%

Question 9

What sort of neurones are GABA neurones generally?

Answer 9

Short inhibitory interneurones, there are some longer tracts: striato-nigral and cerebellar

Question 10

What is the main action of GABA?

Answer 10

Widespread inhibitory action in CNS (both pre and post synaptic

Question 11

What are GABA functions?

Answer 11

Motor activity (cortex, cerebellum and spinal cord)
Extrapyramidal activity (basal ganglia)
Emotional behaviour (limbic system)
Endocrine function (hypothalamus)

Question 12

How is GABA synthesised?

Answer 12

It is formed simply by decarboxylation of glutamate- the enzyme is glutamate decarboxylase

Question 13

Where is GAD only found?

Answer 13

In GABAergic nerve terminals so is a marker of GABA neurones- it is a protein so we can raise antibodies against it and fluorescently label the antibodies

Question 14

Where does glutamate arise from?

Answer 14

Kerb’s cycle

Question 15

What is initial breakdown of GABA by and to?

Answer 15

GABA-T (GABA-transaminase) which breaks it down to succinic semialdehyde

Question 16

What happens to succinic semialdehyde?

Answer 16

It is broken down by SSDH (succinic semialdehyde dehydrogenase) to succinate

Question 17

What happens to succinate after formation?

Answer 17

It goes back into the Kreb cycle

Question 18

What is the synthesis of GABA, utilisation and replacement back into the Kreb’s cycle often referred to as?

Answer 18

The GABA shunt

Question 19

What percentage activity of the Kreb’s cycle gives rise to GABA?

Answer 19

10%- Quite a lot for just one inhibitory neurotransmitter

Question 20

Where is GABA stored?

Answer 20

In vesicles at nerve terminals- it is taken up into vesicles by vesicular transport.

Question 21

What is exocytosis of GABA dependent on?

Answer 21

Calcium

Question 22

What are the two main types of GABA receptor?

Answer 22

GABA-A- type 1- inotropic receptors

GABA-B- type 2- metabotropic receptors (G protein coupled)

Question 23

How is GABA inactivated?

Answer 23

By reuptake and then it is metabolised

Question 24

What are the GABA uptake mechanisms dependent on?

Answer 24

Sodium and energy

Question 25

Where are GABA uptake mechanisms found?

Answer 25

On presynaptic neurones and glial cells

Question 26

What sort of proteins are the GABA uptake mechanisms?

Answer 26

They are protein like receptors but not receptors- just transporters.

Question 27

What sort of enzymes are both GABA transaminase and succinic semialdehyde dehydrogenase?

Answer 27

Mitochondrial enzymes

Question 28

What do inhibitors of GABA metabolism do and what are they used for?

Answer 28

They produce large increase in concentration of GABA in brain- this enhances the action of GABA/ These drugs are used as anticonvulsants e.g. sodium valproate (epilim) and vigabtrin (sabres)

Question 29

How does vigabatrin work?

Answer 29

It is a selective GABA-T inhibitor- it is irreversible (suicide inhibitor)

Question 30

How does sodium valproate work?

Answer 30

It inhibits both GABA-T and SSDH, it is also a pretty useful sodium channel blocker- this imparts anti-convulsant activity as well

Question 31

Where are GABA-A receptors mainly found?

Answer 31

Post-synaptically

Question 32

What type of receptors are GABA-A receptors?

Answer 32

Type 1- pentameric

Question 33

What is the mechanism of GABA-A receptors?

Answer 33

It is a chloride channel causing chloride influx, this causes hyperpolarisation which causes inhibition of firing

Question 34

What agonists of GABA-A are there?

Answer 34

GABA- non selective agonist | Muscimol- selective GABA-A receptor agonist

Question 35

What antagonists of GABA-A are there?

Answer 35

Bicuculline- competitive GABA receptor antagonist Picrotoxin- non competitive Both convulsants with no therapeutic usefulness but useful for experiments

Question 36

Where are GABA-B receptors mainly found?

Answer 36

Pre-synaptically- they sit on GABA nerve terminals

Question 37

What is GABA-B receptor action similar to?

Answer 37

Alpha 2 receptors in noradrenaline system- they act as a negative feedback receptor for GABA- they inhibit neurotransmitter release

Question 38

Where else of GABA-B receptors act?

Answer 38

They also sit on dopaminergic nerve terminals- if GABA is being released in the same area as the dopamine the GABA can interact with GABA-B receptors on dopaminergic terminal and damp down release of dopamine

Question 39

What is the mechanism of action of GABA-B receptors?

Answer 39

They are G protein linked receptors. They cause a decrease in calcium conductance which results in reduction of neurotransmitter release. Stimulation of GABA-B also causes reduction in cAMP (reduces PKA and hence reduces phosphorylation of calcium channels- phosphorylated calcium channels are more permeable than non-phosphorylated)

Question 40

What agonists are there for GABA-B?

Answer 40

GABA | Baclofen- selective

Question 41

What antagonists are there of GABA-B?

Answer 41

Saclofen- competitive GABA-B antagonist

Question 42

What is baclofen used for?

Answer 42

It is used as a useful muscle relaxant and spasmolytic drug- reduces GABA release in spinal cord and reduces activation of alpha motor neurone output- causes relaxation of the skeletal muscles

Question 43

Give a brief summary of how G protein coupling works for a GABA B receptor

Answer 43

When GABA binds to GABA receptor, it changes its conformation and allows receptor to take on board an alpha subunit of the G protein. This alpha subunit normally has GDP bound to it, when it binds to the receptor it exchanges that for GTP. This alpha-GTP is active at the target. The alpha subunit then breaks down GTP back to GDP which inactivates it