Principles of GABA-ergic Transmission

Question 1

What are the two main inhibitory amino acid neurotransmitters?

Answer 1

GABA

Glycine

Question 2

What are the main excitatory amino acid neurotransmitters?

Answer 2

Glutamate
Aspartate
(L-homocysteine – sulphur containing)

Question 3

What type of amino acids are the inhibitory neurotransmitters?

Answer 3

Neutral

Question 4

What type of amino acids are the excitatory neurotransmitters?

Answer 4

Acidic

Question 5

Why is GABA called GABA?

Answer 5

Gamma amino butyric acid

This is because the amino group is on the gamma carbon of GABA

Question 6

Describe the distribution of GABA neurones.

Answer 6

Cerebral cortex 
Cerebellum 
Hippocampus  
Corpus striatum  
Hypothalamus  
Dorsal horn of spinal cord  
Relatively little in the PNS

Question 7

Describe the morphology of GABA neurones.

Answer 7

They are generally short inhibitory interneurons

Question 8

Where do you find longer GABA tracts?

Answer 8

Striato-nigral

Cerebellar

Question 9

What is the main action of GABA neurones?

Answer 9

Widespread inhibitory action in the CNS

Question 10

What are the main functions of GABA neurones in terms of CNS activity?

Answer 10

Emotional control
Motor control
Extrapyramidal activity
Endocrine function

Question 11

What is the precursor for GABA and what enzyme converts it to GABA?

Answer 11

Glutamic acid

Glutamic acid decarboxylase (GAD)

Question 12

Where is this enzyme found?

Answer 12

This enzyme is exclusive to GABA nerve terminals – it is a marker for GABA neurones

Question 13

What product of the Krebs’ cycle gives rise to glutamate?

Answer 13

Alpha-oxoglutarate

Question 14

How is GABA broken down?

Answer 14

Initially by GABA-T (GABA transaminase) to succinic semialdehyde
Succinic semialdehyde is broken down by succinic semialdehyde dehydrogenase (SSDH) to succinate
Succinate then enters the Krebs’ cycle

Question 15

Describe the release of GABA from GABAergic nerve terminals.

Answer 15

Calcium-mediated exocytosis

Question 16

What are the two main GABA receptors and why type of receptorsare they?

Answer 16

GABA-A = type 1 – ionotropic  
GABA-B = type 2 – metabotropic

Question 17

How is GABA inactivated?

Answer 17

By reuptake

Question 18

What are the uptake mechanisms dependent on?

Answer 18

Sodium dependent

Energy dependent

Question 19

Where are the transport proteins for GABA found?

Answer 19

Presynaptic neurones

Glial cells

Question 20

What type of enzymes are the enzymes that break down GABA?

Answer 20

Mitochondrial enzymes

Question 21

What type of enzyme is GAD?

Answer 21

Cytoplasmic enzyme

Question 22

Name two drugs that are used as anti-convulsants that decrease the metabolism of GABA.

Answer 22

Sodium valproate (acts on GABA-T and SSDH (but more so on SSDH)) 
Vigabatrin (selective GABA-T inhibitor)

Question 23

Where are GABA-A receptors found?

Answer 23

Postsynaptic

Question 24

Describe the structure of GABA-A receptors.

Answer 24

They are ionotropic receptors (type 1) 
They have a pentameric structure consisting of the following subunits:
 2 x alpha 
 2 x beta 
 1 x gamma

Question 25

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

Answer 25

GABA binding causes opening of the chloride channel leading to chloride influx
This causes hyperpolarisation of the postsynaptic neurone (inhibitory post-synaptic potential)
This causes inhibition of firing

Question 26

Name two agonists of GABA-A.

Answer 26

GABA

Muscimol

Question 27

Name two antagonist of GABA-A

Answer 27

Bicuculline (competitive antagonist)

Picrotoxin (non-competitive antagonist)

Question 28

What effect do the antagonists have?

Answer 28

They are convulsants

They are used experimentally but not therapeutically

Question 29

Where are GABA-B receptors located?

Answer 29

Presynaptic

Question 30

What is the effect of GABA-B?

Answer 30

It is the negative feedback receptor for GABA release (similar to the effect of alpha-2 receptors on noradrenaline release)

Question 31

What are the two different terms used to describe GABA-B receptors that regulate GABA release and other neurotransmitter release (e.g. dopamine)?

Answer 31

Autoreceptors – when they regulate GABA release

Heteroreceptors – when they regulate the release of other neurotransmitters

Question 32

Describe the mechanism of action of GABA-B receptors.

Answer 32

G protein linked receptor
Causes a decrease in calcium conductance
Reduction in neurotransmitter release
Stimulation of GABA-B also causes a reduction in cAMP

Question 33

Name two agonists of GABA-B receptors.

Answer 33

Baclofen

GABA

Question 34

Name an antagonist of GABA-B receptors.

Answer 34

Saclofen (competitive antagonist)

Question 35

What can GABA-B receptor agonists be used for?

Answer 35

Muscle relaxant and spasmolytic
Mechanism – reduced GABA release in the spinal cord and reduced activation of alpha motor neurone output causes relaxation of skeletal muscles
This reduces spasticity

Question 36

Describe how G-protein coupling works.

Answer 36

GABA binds to the GABA receptor and changes its conformation so that it can bind the alpha subunit of the G protein
The alpha subunit normally has GDP bound to it, when it binds to the receptor it exchanges GDP for GTP
The alpha-GTP subunit is active at the target
The alpha subunit breaks down GTP to GDP, which then inactivates it