NEURO: Neurotransmitter Systems II: GABA and Glycine Flashcards

1
Q

Give examples of Inhibitory Neurotransmitters and what they do?

A

GABA (gamma-aminobutyric acid) and glycine

hyperpolarise the postsynaptic cell, meaning an action potential is less likely to take place ( (ie. to bring it further away from the threshold potential that will induce an action potential).

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2
Q

What are the main mechanisms which cause hyperpolarisation?

A

There are two ways in which ion channels can do this:

  • when the ligand binds, it will allow negative ions (eg. Cl-) to flow in, decreasing the membrane potential
  • when the ligand binds, it will allow K+ ions to flow out, thus decreasing the membrane potential
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3
Q

Describe GABA synthesis and storage.

A

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

It is synthesised in the nerve terminals. Then, it is transported into vesicles by vesicular inhibitory amino acid transporters (VIAATs).

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4
Q

If we were to microscopically look at a nerve terminal/synapse, would we be able to distinguish vesicles holding glutamate or GABA/glycine?

A

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

The different vesicle shapes are due to the electrostatic interactions of the different molecules in the vesicles

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5
Q

Describe the GABA(A) receptor.

Most common GABAa configuration

A

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 is a ligand-gated Cl- channel. It sits in a pentameric structure.

The most common configuration is with 2 α, 2 β and a γ subunit.

The receptor is most commonly found post-synaptically.

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6
Q

GABAa receptor binding sites

A

There are multiple binding sites (on the receptor) for:

  • agonists/antagonists (eg. GABA) [between α & β]
  • benzodiazepines [between α & γ]
  • channel modulators (eg. GA, alcohol)
  • allosteric modulators (eg. barbiturates)
  • channel blockers (eg. picrotoxin)

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

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7
Q

Stimulation of GABAa receptor

A

GABA binds receptor
Cl- channel opens
Cl- influx
Hyperpolarisation

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8
Q

In what ways is GABA activity terminated?

A
  • upon reuptake by GABA reuptake transporter (GAT) on the presynaptic membrane
  • upon breakdown by GABA transaminase
  • upon diffusion away from the synaptic cleft
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9
Q

Describe GABA(B) receptor structure

A

It is a G protein-coupled receptor modulated by the αGi/o G protein cascade.

They exist as dimers, sometimes from two different subtypes (eg. GABA(B1) and GABA(B2))

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

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10
Q

Stimulation of GABAb receptor

A

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

  • activating K+ channels to facilitate K+ efflux
  • blocking Ca2+ influx into the cell
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11
Q

GABA Reuptake

A

neurones and glial contain high-affinity Na+ dependent GABA reuptake transporters (GATs):

  • neurones contain GAT-1
  • glial cells contain GAT-3
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12
Q

GABA Degradation

A

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)

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13
Q

How is GABA implicated in epilepsy?

A

By modulating how much GABA we have in the brain, we can produce the occurrence of seizures.

Epilepsy is a lot of excitation in the brain, so we can amp up the inhibition in different ways that could help us to level out the imbalance in excitation and inhibition.

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14
Q

What is epilepsy?

A

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

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15
Q

Targeting Epilepsy

A

Increase the amount of GABA mediated inhibition to decrease excitation

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16
Q

List some different epilepsy drugs based on their mechanism of action.

A

GABA(A) RECEPTOR ENHANCERS:

  • Barbiturates (not used anymore because of the risk of addiction and overdose)
  • Benzodiazepines
  • Progesterone
  • Ganaloxone

GAT BLOCKERS:
- Tiagabine

GABA-TRANSAMINASE INHIBITOR:
- Vigabatrine

GAD MODULATORS?:

  • Gabapentin
  • Valproate

PRODRUG:
- Progabide (exogenous analogue of glutamate)

17
Q

Anxiety

A

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

18
Q

Describe glycine synthesis and storage.

A

Glycine is synthesised from 3-phosphoglycerate (a product in glycolysis). This gets converted to serine, which then gets converted to glycine in nerve terminals by the enzyme Serine hydroxymethyl-transferase.

It is transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT).

19
Q

Where is glycine most commonly found?

A

in the ventral horn

20
Q

Describe the glycine receptor.

A

It is an ionotropic ligand-gated Cl- ion channel. It is found both pre- and post-synaptically. It has a pentameric structure.

pentameric structure with:

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

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

21
Q

Glycine binding sites

A

The agonist/antagonist binding sites and their requirements are unclear.

22
Q

Glycine receptor modulators

A

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

· Strychnine- plant alkaloid which potently blocks the glycine receptors

23
Q

Glycine reuptake

A

Neurones and glial cells contain high-affinity Na+ dependent glycine re-uptake transporters (GlyTs)
· Glial cells: GlyT-1
· Neurones: GlyT-2

24
Q

Glycine degradation

A

Glycine converted back to serine by Serine hydroxymethyl-transferase

25
Q

What are the mechanisms of glycine activity termination?

A
  • upon the reuptake of glycine by the glycine reuptake transporter Gly1
  • upon break down by glycine decarboxylase
  • upon glycine’s diffusion away from the synaptic cleft
26
Q

Hyperekplexia

A

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

27
Q

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

A

NMDA receptors:

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

Thus, it can increase inhibition (through its own mechanism), but also enhance excitation (due to NMDA receptor activation), making it a complex pharmacological target.

28
Q

What causes hyperekplexia?

A

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

29
Q

Hyperekplexia in goats

A

In startle (or myotonic/fainting) goats, there is a decrease in muscle chloride conductance- this 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.

When the goats/humans have no GABA protein present at the synapses, or the GABA protein is present but isn’t functional, we get the fainting phenomenon.
As a result of the glycine receptor deficiency (or otherwise), they have an inability to produce inhibition.

When their fight or flight response is activated, there is a surge of excitatory and inhibitory signals. However, the inhibitory signals don’t go through, so a transient seizure is induced and they faint.

This phenomenon only really occurs in juvenile goats/humans because the body adapts and upregulates the amount of GABA receptors to compensate.