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LCRS Pharmacology and Therapeutics > GABA-ergic transmission > Flashcards

GABA-ergic transmission Flashcards

1
Q

What are the main inhibitory amino acid neurotransmitters in CNS?

A

GABA

Glycine

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2
Q

What sort of amino acids are inhibitory ones?

A

Neutral

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3
Q

What sort of amino acids are excitatory ones?

A

Acidic

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4
Q

What are the main excitatory amino acids?

A

Glutamate
Aspartate
(L-homocysteine)

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5
Q

Why is GABA given its name?

A

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

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6
Q

Where are GABA neurones found?

A 
Cerebral cortex
Cerebellum
Hippocampus
Corpus striatum
Hypothalamus
Dorsal horn of spinal cord
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7
Q

How much GABA in in the PNS?

A

Relatively little

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8
Q

What percentage of synapses respond to GABA?

A

Large proportion- 30%

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9
Q

What sort of neurones are GABA neurones generally?

A

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

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10
Q

What is the main action of GABA?

A

Widespread inhibitory action in CNS (both pre and post synaptic

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11
Q

What are GABA functions?

A 
Motor activity (cortex, cerebellum and spinal cord)
Extrapyramidal activity (basal ganglia)
Emotional behaviour (limbic system)
Endocrine function (hypothalamus)
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12
Q

How is GABA synthesised?

A

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

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13
Q

Where is GAD only found?

A

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

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14
Q

Where does glutamate arise from?

A

Kerb’s cycle

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15
Q

What is initial breakdown of GABA by and to?

A

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

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16
Q

What happens to succinic semialdehyde?

A

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

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17
Q

What happens to succinate after formation?

A

It goes back into the Kreb cycle

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18
Q

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

A

The GABA shunt

19
Q

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

A

10%- Quite a lot for just one inhibitory neurotransmitter

20
Q

Where is GABA stored?

A

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

21
Q

What is exocytosis of GABA dependent on?

A

Calcium

22
Q

What are the two main types of GABA receptor?

A

GABA-A- type 1- inotropic receptors

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

23
Q

How is GABA inactivated?

A

By reuptake and then it is metabolised

24
Q

What are the GABA uptake mechanisms dependent on?

A

Sodium and energy

25
Q

Where are GABA uptake mechanisms found?

A

On presynaptic neurones and glial cells

26
Q

What sort of proteins are the GABA uptake mechanisms?

A

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

27
Q

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

A

Mitochondrial enzymes

28
Q

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

A

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)

29
Q

How does vigabatrin work?

A

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

30
Q

How does sodium valproate work?

A

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

31
Q

Where are GABA-A receptors mainly found?

A

Post-synaptically

32
Q

What type of receptors are GABA-A receptors?

A

Type 1- pentameric

33
Q

What is the mechanism of GABA-A receptors?

A

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

34
Q

What agonists of GABA-A are there?

A

GABA- non selective agonist

Muscimol- selective GABA-A receptor agonist

35
Q

What antagonists of GABA-A are there?

A

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

36
Q

Where are GABA-B receptors mainly found?

A

Pre-synaptically- they sit on GABA nerve terminals

37
Q

What is GABA-B receptor action similar to?

A

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

38
Q

Where else of GABA-B receptors act?

A

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

39
Q

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

A

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)

40
Q

What agonists are there for GABA-B?

A

GABA

Baclofen- selective

41
Q

What antagonists are there of GABA-B?

A

Saclofen- competitive GABA-B antagonist

42
Q

What is baclofen used for?

A

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

43
Q

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

A

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

LCRS Pharmacology and Therapeutics (33 decks)

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