Neurotransmitter systems II: GABA and Glycine

Question 1

What are the Inhibitory Neurotransmitters?

Answer 1

GABA and glycine

Question 2

Whatdo inhibitory neurotransmitters do?

Answer 2

hyperpolarise the postsynaptic cell, meaning an action potential is less likely to take place

Question 3

What are the main mechanisms which cause hyperpolarisation?

Answer 3

2 main mechanisms which cause hyperpolarisation:

• influx of negatively charged Cl- ions
• efflux of positively charged K+ ions

Question 4

What is the major inhibitory neurotransmitter in the CNS?

Answer 4

GABA (gamma-aminobutyric acid)

Question 5

Describe GABA synthesis.

Answer 5

Glutamate (excitatory) converted to GABA (inhibitory) in the nerve terminals via the action of glutamate decarboxylase (GAD) using a cofactor called pyridoxal phosphate (derived from vitamin B6)

Question 6

Describe GABA storage.

Answer 6

GABA transported into synaptic vesicles by vesicular inhibitory amino acid transporters (VIAAT)

Question 7

What is the Difference in shape between glutamate and GABA synaptic vesicles?

Answer 7

glutamate vesicles are more rounded, whereas GABA vesicles are more oval shaped

Question 8

Describe the structure of the GABAa receptor.

Answer 8

ionotropic ligand-gated Cl- channel

pentameric, consisting of 5 subunits, and each of the subunits has different subtypes:

• Six ⍺ subtypes (⍺1-⍺6)
• Three β subtypes (β1-β3)
• Three 𝛾 subtypes ( 𝛾1-𝛾3)
• Also ẟ,ε,pi, theta subunits

Question 9

Describe the Stimulation of GABAa receptor.

Answer 9

GABA binds receptor
Cl- channel opens
Cl- influx
Hyperpolarisation

Question 10

What is the Most common GABAa configuration?

Answer 10

2alpha
2beta
gamma

Question 11

Where are GABAa receptors located?

Answer 11

post-synaptically

Question 12

Describe the GABAa receptor binding sites.

Answer 12

The GABAa receptor has multiple binding sites:
· Agonists/Antagonists (e.g. GABA): binds between alpha and beta subunits
· Benzodiazepine binding site: binds between alpha and gamma subunits
· Channel blockers (e.g. picrotoxin): block the channel and prevent ion flow
· Channel modulators (e.g. GA)
· Allosteric modulators (e.g. barbiturates)

*because GABAa has multiple binding sites, it makes an attractive drug target for multiple disorders (e.g. epilepsy)

Question 13

Describe the process of GABA reuptake?

Answer 13

After GABA has been released into synaptic cleft and binds GABA receptors on post-synaptic membrane, GABA is reuptaken by the presynaptic terminal via the GABA reuptake transporter (GAT)
neurones and glial contain high-affinity Na+ dependent GABA reuptake transporters (GATs):

• neurones contain GAT-1
• glial cells contain GAT-3

Question 14

Describe the process of Stimulation of GABAb receptor.

Answer 14

GABA binds GABAb receptor (Gi/o) causing hypoerpolarisation by:

• activating K+ channels to facilitate K+ efflux
• blocking Ca2+ influx into the cell

Question 15

Describe the structure of the GABAb receptor.

Answer 15

metabotropic G-protein coupled receptor (Gi/o):
· Extracellular Venus Flytrap Domain: for ligand binding
· 7 Transmembrane Domains
· Intracellular C-terminal Domain: coupled to a G-protein (Gi/o)

forms dimers:
-heteromers: GABAb1 & GABAb2

Question 16

Describe the process of GABA Degradation.

Answer 16

1) GABA is degraded via an enzyme called GABA transaminase (GABA-T) into a compound called Succinic semialdehyde.
2) Succinic semialdehyde then converted into Succinic acid via an enzyme called Succinic semialdehyde dehydrogenase (SSADH)

Question 17

What is epilepsy?

Answer 17

brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurones
-TOO MUCH EXCITATION

Question 18

How is epilepsy targeted?

Answer 18

Increase the amount of GABA mediated inhibition to decrease excitation

Question 19

What is Anxiety?

Answer 19

feeling of unease (e.g. worry or fear) which can range from mild to severe
-can be normal or pathological

Question 20

What is the second major inhibitory neurotransmitter in the CNS?

Answer 20

Glycine

Question 21

Where is glycine most commonly found?

Answer 21

in the ventral horn

Question 22

Describe the process of Glycine Synthesis.

Answer 22

Via Glycolysis:

-serine converted to glycine in nerve terminals by enzyme Serine hydroxymethyl-transferase

Question 23

Describe the process of Glycine storage.

Answer 23

glycine transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT), like GABA

Question 24

What is a Glycine receptor.

Answer 24

ionotropic ligand gated Cl- channel

>binding of glycine will lead to opening of the channel and an influx of Cl- ions, causing hyperpolarisation

Question 25

Describe the Glycine receptor structure.

Answer 25

pentameric structure with:

• Four ⍺ subtypes (⍺1-⍺4)
• One β subtypes
• most common configuration is:
• 3⍺, 2β
• 4⍺, 2β

Question 26

What is known about Glycine binding sites?

Answer 26

agonist/antagonist binding sites are unclear

Question 27

What is the function of Glycine receptor modulators?

Answer 27

modulators of this receptor lag behind the GABA receptor, although there is one known modulator:

· Strychnine- plant alkaloid which potently blocks the glycine receptors

Question 28

Where are glycine receptors found?

Answer 28

pre-synaptically and post-synaptically

Question 29

Describe the process of Glycine reuptake.

Answer 29

Neurones and glial cells contain high-affinity Na+ dependent glycine re-uptake transporters (GlyTs)

· Glial cells: GlyT-1

· Neurones: GlyT-2

Question 30

Describe the process of Glycine degradation.

Answer 30

Glycine converted back to serine by Serine hydroxymethyl-transferase

Question 31

What is Hyperekplexia?

Answer 31

rare disorder characterised by hypertonia (increased muscle tone) and an exaggerated startle response

Question 32

Other than glycine receptors, what other receptors can glycine stimulate?

Answer 32

NMDA receptors:

• Glutamate binds to the GluN2 subunits
• Glycine or D-serine binds to the GluN1 subunit

Question 33

What causes hyperekplexia?

Answer 33

Gene mutations (e.g. glycine receptors or transporters) disrupt normal inhibitory glycinergic neurotransmission, leading to neuronal hyperexcitability due to impaired glycingergic inhibition

Question 34

Describe Hyperekplexia in goats.

Answer 34

In startle (or myotonic/fainting) goats, there is a decrease muscle chloride conductance- can be caused by glycine receptor mutations.

As the goats mature, GABAa receptors (ligand gated Cl- channels) are upregulated to compensate glycine receptor mutations/deficiency.