GABA

Question 1

What type of neurotransmitter is GABA?

Answer 1

Inhibitory.

Question 2

How does GABA act to inhibit action potential conductance?

Answer 2

GABA hyperpolarises the postsynaptic neurone, taking the action potential away from the threshold for firing.

Question 3

What type of neurones are GABA neurones?

Answer 3

Interneurones; short distance, locally connective and active neurones.

Question 4

In what region does GABA release control the activity of neurones?

Answer 4

In the region of the neurone from which it was released.

Question 5

Describe the synthesis of GABA.

Answer 5

GABA is synthesised from glutamate by the enzyme glutamic acid decarboxylase (GAD).

Question 6

Where is GAD found? Why is this useful?

Answer 6

GAD is found only in those neurones which synthesise GABA and thus the location of GAD is a valuable indicator of GABAergic neurones.

Question 7

How is GABA metabolised?

Answer 7

GABA is metabolised by the ubiquitous enzyme GABA transaminase (GABA-T).

Question 8

Why do GABA levels rise in the brain after death? How is this useful?

Answer 8

GAD is anaerobic whereas GABA-T is aerobic thus after death, levels of GABA in the brain increase very rapidly. This can be used to determine the time of death.

Question 9

What effect do GAD inhibitors have on a patient? Why?

Answer 9

Inhibitors of GAD will cause a decrease in the levels of GABA in the brain and will cause convulsions. This is due to an increase in global excitation (lack of inhibition of neurone activity).

Question 10

How are GABA and glycine stored?

Answer 10

Both GABA and glycine appear to be stored in synaptic vesicles and their released is by calcium-dependent exocytosis.

Question 11

How are GABA and glycine removed from the synaptic cleft?

Answer 11

By active reuptake.

Question 12

Describe glycine receptors.

Answer 12

Glycine receptors are ionotropic receptors; ligand binding causes a conformational change in an ion channel which lets ions through down their concentration gradient.

Question 13

What type of receptors are GABA-A receptors?

Answer 13

Ionotropic, allowing the passing of chloride ions.

Question 14

What type of receptors are GABA-B receptors?

Answer 14

Metabotropic, causing changes in the metabolism of the cell by binding to GPCRs and triggering second messengers.

Question 15

Where are glycine receptors most commonly found?

Answer 15

The spinal cord.

Question 16

Name an antagonist of the glycine receptor.

Answer 16

The convulsant drug strychnine is a competitive glycine antagonist, strychnine can also cause death by asphyxiation.

Question 17

How many subunits make up the glycine receptor? What subtypes are these?

Answer 17

5 sub-units. 3 alpha and 2 beta.

Question 18

What is the range of the affinity of strychnine to the glycine receptor?

Answer 18

5-15nM.

Question 19

What ion channels are GABA-A receptors directly coupled to?

Answer 19

Chloride ion channels.

Question 20

Where are GABA-A receptors mainly found?

Answer 20

Postsynaptically.

Question 21

How does GABA-A receptor activation affect neuronal excitability?

Answer 21

It reduces it.

Question 22

Name a competitive antagonist of the GABA-A receptor.

Answer 22

Bicuculline.

Question 23

What is the main action of GABA-B receptors?

Answer 23

Presynaptic inhibition.

Question 24

What is the effect of GABA-B receptor activation?

Answer 24

Activation of second messengers, linking and blocking calcium ion channels, preventing calcium dependent exocytosis and neurotransmitter release.

Question 25

Name an antagonist of the GABA-B receptor.

Answer 25

Baclofen.

Question 26

What are antagonists of the GABA-B receptor?

Answer 26

Phaclofen, 1-OH saclofen, and CGP38393.

Question 27

What GABA receptor is the major inhibitory amino acid receptor in the brain?

Answer 27

GABA-A.

Question 28

In development, what is different about the GABA-A receptor?

Answer 28

In development (<10), the chloride gradient is in the opposite direction, leading to an excitatory effect upon activation.

Question 29

What pharmacological actions are GABA-A receptors involved in?

Answer 29

Sedation, anxiety, muscle relaxation, convulsive activity, amnesia.

Question 30

Which GABA-A active drug is a valuable pre-anaesthetic?

Answer 30

Midazolam.

Question 31

GABA-A receptors have binding sites for which drugs?

Answer 31

Benzodiazepines, barbiturates, neurosteroids.

Question 32

What effect do benzodiazepines have when they bind to the GABA-A receptor?

Answer 32

Potentiate action of GABA by shorting the GABA dose-response curve to the left. Don’t need as much GABA to produce the same response. Increase the frequency of channel opening.

Question 33

What effect do barbiturates have when they bind to the GABA-A receptor?

Answer 33

Potentiate actions of GABA by shifting the dose-response curve to the left and increasing the maximum response. Increase channel open lifetime.

Question 34

What effect do neuropeptides have when they bind to the GABA-A receptor?

Answer 34

Increase channel opening frequency and open lifetime.

Question 35

How many isoforms are there of the alpha subunit of the GABA-A receptor?

Answer 35

6.

Question 36

How many isoforms are there of the beta subunit of the GABA-A receptor?

Answer 36

3

Question 37

How many isoforms are there of the gamma subunit of the GABA-A receptor?

Answer 37

3

Question 38

The most common GABA-A receptor in the human brain consists of which sub-units?

Answer 38

Alpha-1, Beta-2, Gamma-2.

Question 39

What can be inferred by the presence of specific receptor sub-types?

Answer 39

The synaptic location of the receptor.

Question 40

Where are GABA-A receptors with gamma subunits commonly found?

Answer 40

Extrasynaptically.

Question 41

What are alpha GABA-A sub-units important for?

Answer 41

The recognition of the benzodiazepines.

Question 42

What are beta GABA-A sub-units important for?

Answer 42

Recognition of the natural agonist GABA.

Question 43

What effect does activation of post-synaptic GABA-B receptors have?

Answer 43

Activation of the receptors located postsynaptically produces a long-lasting hyperpolarisation by increasing potassium conductance (increasing negativity).

Question 44

Which protein sub-units form the GABA-B receptor?

Answer 44

GABA-B-R1 and GABA-B-R2

Question 45

What physiological actions are GABA-B receptors involved in?

Answer 45

Control of epilepsy, regulation of the HPA, enhancement of antidepressant drug action, suppression of cocaine withdrawal symptoms, alleviation of pain.

Question 46

Describe the structure of GABA-A receptors. What type of receptor are they?

Answer 46

GABA-A receptors are ionotropic receptors coupled to Cl- ion channels. They are pentamers consisting of α, β and γ subunits. The most common GABA-A receptor is made of 2α, 2β and 1γ subunit.

Question 47

Where do GABA and benzodiazepines bind to a GABA-A receptor?

Answer 47

GABA binds at the interface between α and β subunits, whereas benzodiazepines bind at the interface between α and γ subunits.

Question 48

Where are GABA receptors found? Explain what happens when they are activated (refer to inhibitory action)?

Answer 48

GABA-A receptors are found post-synaptically and upon activation, they open Cl- channels. This increases Cl- conductance so Cl- ions enter the cell causing the cell to become hyperpolarised below the resting membrane potential. This hyperpolarization makes it harder for the cell to reach the threshold potential, therefore making it harder to fire an action potential. This causes an inhibitory effect in the post-synaptic neurone

Question 49

Describe the structure of GABA-B receptors. What type of receptor are they?

Answer 49

GABA-B receptors are metabotropic receptors coupled to second messenger systems. They are heterodimers considering of the GABA-B-R1 and the GABA-B-R2 subunits. Both subunits are 7 transmembrane proteins and must be expressed together to give a functioning receptor.

Question 50

Explain what happens when presynaptic GABA-B receptors are activated.

Answer 50

Upon activation they inhibit adenylate cyclase, stopping the conversion of ATP to cAMP. This stops the phosphorylation of Ca2+ channels, so they remain closed, stopping Ca2+ from entering the cell, and therefore stopping the Ca2+ dependent release of GABA. This gives an inhibitory presynaptic effect reducing the release of GABA.

Question 51

Explain what happens when postsynaptic GABA-B receptors are activated.

Answer 51

GABAB receptors may also be found post-synaptically where they increase K+ conductance, hyperpolarizing the cell, and thereby reducing action potential firing.