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 (glutamate)

Glutamic acid decarboxylase (GAD)

Question 12

Where is this enzyme (GAD) 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

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

Answer 15

GABA-A = type 1 – ionotropic  
GABA-B = type 2 – metabotropic- (g protein)

Question 16

How is GABA inactivated?

Answer 16

By reuptake

Question 17

What are the GABA reuptake mechanisms dependent on?

Answer 17

Sodium dependent

Energy dependent

Question 18

Where are the transport proteins for GABA found?

Answer 18

Presynaptic neurones

Glial cells

Question 19

What type of enzyme is GAD?

Answer 19

Cytoplasmic enzyme

Question 20

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

Answer 20

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

Vigabatrin (selective GABA-T inhibitor)

Question 21

Where are GABA-A receptors found?

Answer 21

Postsynaptic

Question 22

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

Answer 22

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 23

Name two agonists of GABA-A.

Answer 23

GABA

Muscimol

Question 24

Name two antagonist of GABA-A

Answer 24

Bicuculline (competitive antagonist)

Picrotoxin (non-competitive antagonist)

Question 25

What effect do the GABA antagonists have?

Answer 25

They are convulsants They are used experimentally but not therapeutically

Question 26

Where are GABA-B receptors located?

Answer 26

Presynaptic

Question 27

What is the effect of GABA-B?

Answer 27

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

Question 28

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

Answer 28

Autoreceptors – when they regulate GABA release Heteroreceptors – when they regulate the release of other neurotransmitters

Question 29

Describe the mechanism of action of GABA-B receptors.

Answer 29

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 30

Name two agonists of GABA-B receptors.

Answer 30

Baclofen GABA

Question 31

Name an antagonist of GABA-B receptors.

Answer 31

Saclofen (competitive antagonist)

Question 32

What can GABA-B receptor agonists be used for?

Answer 32

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 33

Describe how G-protein coupling works. (GABA-B)

Answer 33

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