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Neurology > Neurotransmitters Systems II: GABA & Glycine > Flashcards

Neurotransmitters Systems II: GABA & Glycine Flashcards

1
Q

What are the criteria required for a molecule to be classed as a neurotransmitter?

A

The molecule must be synthesised and stored in the presynaptic neuron

The molecule must be released by the presynaptic axon terminal upon stimulation

The molecule must produce a response in the postsynaptic cell

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2
Q

What is the effect of inhibitory neurotransmitters?

A

Inhibitory neurotransmitters (e.g. GABA) can cause neuronal membrane hyperpolarisation - displacement of a membrane potential towards a more negative value

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3
Q

Explain the events that occur in a depolarisation

A

Resting potential -70mV

in a depolarisation event caused by Na+, membrane potential becomes more positive (~90mV) to trigger an action potential

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4
Q

What is hyperpolarisation?

A

Hyperpolarization involves the resting potential (-70mV) becoming more (hyper-) negative - action potential less likely to occur

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5
Q

What are the 2 mechanisms that cause hyperpolarisation?

A

2 main mechanisms cause hyperpolarisation:

  1. Influx of Cl-
  2. K+ efflux
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6
Q

Explain how Cl- influx causes hyperpolarisation

A

Negatively charged Cl- ions flow into the cell (facilitated by GABA)

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7
Q

How does K+ efflux lead to hyperpolarisation?

A

Moving positive K+ ions out of the cell causing the inside of the cell to become more negative

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8
Q

What is GABA?

A

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS)

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9
Q

Where is GABA most commonly known to induce its inhibitory effects?

A

GABA most commonly found as an inhibitory neurotransmitter in local circuit interneurons

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10
Q

How many synapses of the body does GABA have an effect on?

A

Approximately one third of synapses utilise GABA as their inhibitory neurotransmitter

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11
Q

How can we differentiate GABA and glutamate vesicles?

A

Glutamate is carried in round vesicles

GABA is transported in oval vesicles

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12
Q

Outline the synthesis of GABA

A

GABA synthesis from glutamate via Glutamate decarboxylase (GAD) enzyme action and a cofactor called Pyridoxal Phosphate (Vit. B6 derived)
=> OH group removed from glutamate to form GABA

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13
Q

Where is GABA synthesised?

A

Synthesised in the nerve terminals

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14
Q

How is GABA put in to vesicles?

A

Transported into vesicles by GABA transporters called vesicular inhibitory amino acid transporters (VIAAT)

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15
Q

Name the 2 major GABA receptors?

A

GABAa

GABAb

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16
Q

What type of receptor is GABAa?

A

The GABAₐ receptor is a ligand Gated Cl⁻ Channel

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17
Q

What happens when the GABAa receptor is stimulated?

A

When activated the channel opens allowing the movement of Cl- ions
=> causes hyperpolarisation

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18
Q

Explain how GABAa activation causes hyprpolarisation?

A

Resting potential (-70mV)
Cl- ions enter the cell when GABA binds to GABAₐ receptor
Causes hyperpolarisation - more negative membrane potential (-90mV)

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19
Q

Describe the structure of the GABAa receptor

A

The receptor is a pentameric structure:

Six 𝛂 subtypes (𝛂1-3)
Three ꞵ subtypes (ꞵ1-3) →
Three ɣ subtypes (ɣ1-3)
Also ε π ẟ θ subunits

2𝛂 and 2ꞵ ɣ most common configuration

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20
Q

How is GABAa activity regulated?

A

GABA activity terminated upon retake by GABA reuptake transporter GAT (EAAT for glutamate)

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21
Q

What are the different binding sites on the GABAa receptor?

A

Multiple binding sites on the GABAₐ receptor:

Agonists / antagonists e.g. GABA

Benzodiazepine binding site

Channel modulators e.g. GA, alcohol

Allosteric modulators e.g.

Barbiturates

Channel blockers e.g. Picrotoxin

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22
Q

Which part of the synaptic terminal are GABAa receptors found?

A

GABAₐ receptors are predominantly postsynaptic

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23
Q

Explain how GABA is transported across the synapse

A
  1. When GABA is released from its vesicles, it binds to its
    GABAₐ receptor
  2. GABA molecules then diffuse away once they’ve
    activated their receptors

3, GABA is reuptaken into the presynaptic terminal

  1. Reuptake carried out by GAT
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24
Q

What kind of receptor is the GABAb receptor?

A

A metabotropic GPCR (similar to GLUT)

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25
Q

Describe the structure of the GABAb receptor

A

An extracellular large venus fly trap domain for ligand binding
7 transmembrane domain
Intracellular C terminal domain

26
Q

Explain how the structure of GABAb receptors is altered on binding

A

GABAᴃ receptors form dimers which can be heteromers of GABAᴃ₁ and GABAᴃ₂ upon binding

27
Q

What are the effects of GABAb receptor binding?

A

GABAᴃ GPCRs are coupled to G proteins Gi/Go
GABAᴃ receptor activates K+ channels to facilitate efflux
The receptors also block Ca2+ influx into the cell

28
Q

How does GABA reuptake occur?

A

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

Neurons = GAT-1
Glial cells = GAT-3

29
Q

How does degradation of GABA occur?

A

Degradation of GABA occurs via 2 enzymes:

(GABA-T) GABA transaminase:
degrades GABA into succinic semialdehyde

(SSADH) succinic semialdehyde dehydrogenase
enzyme converts Semialdehyde → succinic acid

30
Q

Explain the significance of GABA and glutamate

A

GABA and glutamate are the major neurotransmitters in the brain – both work together to control the brain’s overall level of excitation.
Glutamate is the excitatory neurotransmitter
GABA is an inhibitory neurotransmitter

Remarkably, in one step, the major excitatory neurotransmitter in the brain is converted into the major inhibitory neurotransmitter in the brain!

31
Q

What is epilepsy?

A

Epilepsy is a brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurons

Too much excitation → increase inhibition

32
Q

What type of drugs are used to combat epilepsy?

A
  • GABAa receptor enhancers
  • GAT blockers
  • GABAT inhbitors
  • GAD modulators
  • Prodrugs
33
Q

Give examples of GABAa enhancers used to treat epilepsy

A

Barbiturates
Bezodiazepines
Progesterone
Ganaloxone

34
Q

Name a GAT blocker given to epileptic patients

A

Tiagabine

35
Q

Name a GABAT inhbiitor used in epilepsy

A

Vigabatrine - decreases amount of GABA available to decrease excitation

36
Q

How does enhancing GABA receptors inhibit excitation seen in epilepsy?

A

Enhancing GABA neurotransmission, increases inhibition => decreasing excitation

37
Q

What is a prodrug?

A

e.g. Progabide

inactive precursor of GABA activated within the body to serve as an inhibitory neurotransmitter

38
Q

What is anxiety?

A

Anxiety can be defined as a feeling of unease (e.g. worry or fear), which can range from mild to severe – can be normal or pathological

39
Q

What are the different forms of anxiety?

A

Anxiety disorders - (e.g. generalised anxiety disorder, panic disorder)

40
Q

What are anxiolytics?

A

Anxiolytics - (e.g. barbiturates, benzodiazepines – GABAA receptor)
decrease anxiety levels

41
Q

What is glycine?

A

Glycine is the second major inhibitory neurotransmitter in the central nervous system (CNS)

42
Q

Where is Glycine most commonly found?

A

Glycine most commonly found as an inhibitory neurotransmitter in the ventral horn, the location for spinal interneuron terminals.

However, our understanding of the glycine receptor is lagging behind the GABA receptors – in part due to limited allosteric modulators of the receptor

43
Q

Where is glycine synthesised?

A

Synthesised in the nerve terminals

44
Q

Outline glycine systhesis

A

Glycine synthesis occurs via glycolysis involving many enzymes including Serine hydroxymethyl-transfrase causing Serine → glycine

45
Q

How is glycine transported to vesicles?

A

Transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT)

46
Q

What type of receptor is the glycine receptor?

A

Is also a ligand gated Cl- channel

47
Q

What is the result of glycine binding to its receptor?

A

Binding of Glycine will lead to the channel opening

Causing an influx of Cl- ions
=> hyperpolarisation

48
Q

Describe the structure of the glycine receptor

A

Pentameric structure
Four 𝛂 subunits (𝛂1 - 𝛂4)
One ꞵ subtype
3𝛂₁2ꞵ or 4𝛂₁ꞵ most common configuration

49
Q

Where is the antagonist binding site on the glycine receptor?

A

Agonist / antagonist binding sites unclear - although plant alkaloid strychnine potently
blocks glycine receptors

50
Q

Where on the synapse are glycine receptors located?

A

Glycine receptors are found both pre and postsynaptically

51
Q

Describe the synaptic events occuring due to glycine

A
  1. Once glycine molecules bind to their receptors they can
    diffuse away
  2. They are reuptaken by Glycine reuptake transporter
52
Q

How is a glycine response mediated?

A

Glycine activity terminated upon retake by glycine reuptake transporter GlyT

53
Q

Which receptors does glycine bind to?

A

Glycine receptors

NMDA glutamate receptors

54
Q

Where on the NMDA receptor does glycine bind?

A

Glutamate binds to the GluN2 subunit
Glycine/ D serine can bind to the GluN1 subunit
=> removes the Mg2+ block

55
Q

Explain how the reuptake of glycine occurs?

A

Neurons and glial contain high-affinity Na+ dependent glycine reuptake transporters (GlyTs)
Glial cells = GlyT-1
Neurons = GlyT-2

56
Q

How is glycine degraded?

A

Various enzymes responsible for the breakdown of glycine – including the reversal of glycine biosynthesis:

Glycine can be converted back into serine via Serine hydroxymethyl-transferase

57
Q

What is Hyperekplexia?

A

Hyperekplexia is a rare disorder characterised by hypertonia (increased muscle tone) and an exaggerated startle response.

Symptoms can manifest in relation to unexpected stimuli (e.g. loud noises)

58
Q

How does glycine play a role in Hyperekplexia?

A
  • Gene mutations (e.g. glycine receptors, glycine
    transporters) can disrupt normal glycinergic
    neurotransmission.
  • Can lead to neuronal hyperexcitability (by impairing
    glycinergic inhibition).
  • Leads to hypertonia and exaggerated startle response.
59
Q

Why is there an excess of GABAa receptors in startle goats?

A

In startle goats, there is a decreased muscle chloride conductance – can be caused by glycine receptor mutations - Glycine receptor deficiency
As the goats mature GABAᴀ receptors are upregulated to compensate

60
Q

What is the major inhibitory neurotransmitter in the body?

A

GABA is the major inhibitory neurotransmitter in the CNS. GABA binds to the ionotropic GABAa receptors and the metabotropic GABAb receptors.

61
Q

What is the secondary inhibitory neurotransmitter?

A

Glycine is the second major inhibitory neurotransmitter in the CNS. Glycine binds to ionotropic glycine receptors – pentamers consisting of mixtures of four α- and one β-subunit

62
Q

What is the significance of drugs affecting GABA neurotransmission?

A

Drugs targeting GABA neurotransmission can be used to treat symptoms of epilepsy and anxiety

Neurology (20 decks)

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