GABA-ergic transmission Flashcards
What are the main inhibitory amino acid neurotransmitters in CNS?
GABA
Glycine
What sort of amino acids are inhibitory ones?
Neutral
What sort of amino acids are excitatory ones?
Acidic
What are the main excitatory amino acids?
Glutamate
Aspartate
(L-homocysteine)
Why is GABA given its name?
The amino group is on the gamma carbon and the carboxylic acid is on the alpha carbon
Where are GABA neurones found?
Cerebral cortex Cerebellum Hippocampus Corpus striatum Hypothalamus Dorsal horn of spinal cord
How much GABA in in the PNS?
Relatively little
What percentage of synapses respond to GABA?
Large proportion- 30%
What sort of neurones are GABA neurones generally?
Short inhibitory interneurones, there are some longer tracts: striato-nigral and cerebellar
What is the main action of GABA?
Widespread inhibitory action in CNS (both pre and post synaptic
What are GABA functions?
Motor activity (cortex, cerebellum and spinal cord) Extrapyramidal activity (basal ganglia) Emotional behaviour (limbic system) Endocrine function (hypothalamus)
How is GABA synthesised?
It is formed simply by decarboxylation of glutamate- the enzyme is glutamate decarboxylase
Where is GAD only found?
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
Where does glutamate arise from?
Kerb’s cycle
What is initial breakdown of GABA by and to?
GABA-T (GABA-transaminase) which breaks it down to succinic semialdehyde
What happens to succinic semialdehyde?
It is broken down by SSDH (succinic semialdehyde dehydrogenase) to succinate
What happens to succinate after formation?
It goes back into the Kreb cycle
What is the synthesis of GABA, utilisation and replacement back into the Kreb’s cycle often referred to as?
The GABA shunt
What percentage activity of the Kreb’s cycle gives rise to GABA?
10%- Quite a lot for just one inhibitory neurotransmitter
Where is GABA stored?
In vesicles at nerve terminals- it is taken up into vesicles by vesicular transport.
What is exocytosis of GABA dependent on?
Calcium
What are the two main types of GABA receptor?
GABA-A- type 1- inotropic receptors
GABA-B- type 2- metabotropic receptors (G protein coupled)
How is GABA inactivated?
By reuptake and then it is metabolised
What are the GABA uptake mechanisms dependent on?
Sodium and energy
Where are GABA uptake mechanisms found?
On presynaptic neurones and glial cells
What sort of proteins are the GABA uptake mechanisms?
They are protein like receptors but not receptors- just transporters.
What sort of enzymes are both GABA transaminase and succinic semialdehyde dehydrogenase?
Mitochondrial enzymes
What do inhibitors of GABA metabolism do and what are they used for?
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)
How does vigabatrin work?
It is a selective GABA-T inhibitor- it is irreversible (suicide inhibitor)
How does sodium valproate work?
It inhibits both GABA-T and SSDH, it is also a pretty useful sodium channel blocker- this imparts anti-convulsant activity as well
Where are GABA-A receptors mainly found?
Post-synaptically
What type of receptors are GABA-A receptors?
Type 1- pentameric
What is the mechanism of GABA-A receptors?
It is a chloride channel causing chloride influx, this causes hyperpolarisation which causes inhibition of firing
What agonists of GABA-A are there?
GABA- non selective agonist
Muscimol- selective GABA-A receptor agonist
What antagonists of GABA-A are there?
Bicuculline- competitive GABA receptor antagonist
Picrotoxin- non competitive
Both convulsants with no therapeutic usefulness but useful for experiments
Where are GABA-B receptors mainly found?
Pre-synaptically- they sit on GABA nerve terminals
What is GABA-B receptor action similar to?
Alpha 2 receptors in noradrenaline system- they act as a negative feedback receptor for GABA- they inhibit neurotransmitter release
Where else of GABA-B receptors act?
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
What is the mechanism of action of GABA-B receptors?
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)
What agonists are there for GABA-B?
GABA
Baclofen- selective
What antagonists are there of GABA-B?
Saclofen- competitive GABA-B antagonist
What is baclofen used for?
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
Give a brief summary of how G protein coupling works for a GABA B receptor
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
