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Cellular Neuroscience > GABA and Glycine > Flashcards

GABA and Glycine Flashcards

1
Q

What type of NT is GABA?

A

Amino acid.

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2
Q

What type of NT is glycine?

A

Amino acid.

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3
Q

How is GABA synthesised?

A

Glutamic acid decarboxylase (GAD) removes a carboxyl group from glutamate to convert it into GABA.

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4
Q

Why can the presence of GAD be used as a marker to identify GABAergic neurons?

A

GAD is only found in neurons that synthesise GABA.

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5
Q

Where in the brain is GABA located?

A

In highly diverse inhibitory interneurons and projection neurons throughout the brain.

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6
Q

What is the role of GAT-1 in the first pathway for the inactivation of GABAergic transmission?

A

It transports GABA back into GABAergic terminals after it was released by exocytosis.

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7
Q

What is the role of vGAT in the first pathway for the inactivation of GABAergic transmission?

A

It pumps GABA back into vesicles in the GABAergic terminals.

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8
Q

What is the role of GABA transaminase (GABA-T) in the first pathway for the inactivation of GABAergic transmission?

A

It degrades GABA into succinic semialdehyde (SSA).

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9
Q

Describe what happens to SSA in the first pathway for the inactivation of GABAergic transmission.

A

It is converted to succinate by succinate semialdehyde dehydrogenase (SSADH).

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10
Q

Describe what happens to succinate in the first pathway for the inactivation of GABAergic transmission.

A

It cascades through the citric acid cycle to become alpha-ketoglutarate, which can be converted into glutamate.

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11
Q

How is GABAc pharmacologically distinct from GABAa?

A

GABAc can be activated by cis-4-aminobut-2-enoate (CACA) but GABAa cannot.
Classic GABAa agonists, e.g. isoguvacine, have no effect on GABAc.

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12
Q

Why might GABAc just be a variant of GABAa?

A

GABAc is a homomeric complex of “rho” subunits sharing a considerable amino acid sequence homology with the remaining GABAa subunits.

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13
Q

How is the net flow of GABA from GABAergic neurons to astrocytes offset in the second pathway for the inactivation of GABAergic transmission?

A

There is a steady flow of astrocytic glutamine (GABA precursor) into GABAergic terminals.

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14
Q

Describe how glutamine is converted into GABA in the second pathway for the inactivation of GABAergic transmission?

A

Glutaminase converts glutamine into glutamate.
GAD converts glutamate into GABA.

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15
Q

Which GABA receptor(s) are ionotropic?

A

GABAa and GABAc.

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16
Q

Which GABA receptor(s) are metabotropic?

A

GABAb.

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17
Q

Are GABA receptors located presynaptically or postsynaptically?

A

Both.

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18
Q

How do GABAb receptors cause presynaptic inhibition?

A

They suppress calcium influx and reduce NT release.

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19
Q

How do GABAb receptors cause postsynaptic inhibition?

A

They activate potassium currents that hyperpolarise the cell.

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20
Q

How do GABAa receptors cause inhibition?

A

The inward chloride currents that go through GABAa receptors contribute to membrane inhibition via IPSCs evoked in presynaptic terminals or in postsynaptic cells.

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21
Q

Describe the composition of GABAa receptors.

A

It is a pentameric complex comprised of possibly more than 2000 different subunit combinations.

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22
Q

How many subunits and subunit families do GABAa receptors have?

A

19 different subunits in 8 families.

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23
Q

Which is the most prevalent GABAa subunit?

A

Alpha-1 (a1).

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24
Q

Which is the most prevalent GABAa subtype?

A

Alpha-1, beta-2, gamma-2 (a1B2y2).

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25
Q

Where is the a2 GABAa subunit most abundant?

A

Regions where a1 is absent.

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26
Q

Where is the a3 subunit expressed?

A

Regions complementary to a1.

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27
Q

Where is the a6 subunit expressed?

A

Almost exclusively in the cerebellum.

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28
Q

Why do receptors have different subunit compositions?

A

To have different functional characteristics.

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29
Q

What is the function of alpha GABAa subunits?

A

Recognition of benzodiazepines.

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30
Q

What is the function of beta GABAa subunits?

A

Recognition of GABA (endogenous agonist).

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31
Q

What is the function of gamma GABAa subunits?

A

It is a structural subunit that interacts with the PSD to keep the receptor anchored in the membrane.

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32
Q

Which ion is the channel pore of GABAa receptors specific to?

A

Chloride ions.

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33
Q

What does GABAa activation produce at inhibitory synapses?

A

IPSP (inhibitory postsynaptic potential).

34
Q

What are the two agonists of GABAa receptors?

A

GABA.
Muscimol.

35
Q

What is the antagonist of GABAa receptors?

A

Bicuculline.

36
Q

What is the channel blocker for GABAa receptors?

A

Picrotoxin.

37
Q

Briefly describe the process of IPSP production.

A

NT binds to GABA receptor.
GABA receptor undergoes conformational change.
Ion channel pore opens.
Influx of chloride ions into the postsynaptic cell.
Membrane potential is repolarised towards RMP or hyperpolarised.

38
Q

Name all 8 subunit families for GABAa and how many subunits each contains.

A

Alpha (a) = 6.
Beta (B) = 3.
Gamma (y) = 3.
Rho (p) = 3.
Delta (S) = 1.
Epsilon (E) = 1.
Theta (0) = 1.
Pi = 1.

39
Q

Which GABAa subunits can form heteromeric complexes?

A

Alpha, beta, gamma, delta and epsilon.

40
Q

Describe the GABAa/c receptor’s formation and pharmacological properties.

A

Homomeric complex of rho-subunits.
Expressed in the retina.
Resistant to bicuculline and baclofen.

41
Q

Where in the body is the pi-subfamily expressed?

A

Reproductive organs.

42
Q

Where do inhibitory interneurons often make axosomatic synpases?

A

Close to the axon hillock.

43
Q

How can IPSPs attenuate the excitatory effects of EPSPs?

A

A hyperpolarising IPSP makes it more difficult for excitatory inputs to bring the membrane potential to threshold.

44
Q

GABAa receptors can be targeted by which four classes of drugs?

A

Benzodiazepines.
Barbiturates.
Neurosteroids.
General anaesthetics.

45
Q

How do drugs interact with GABAa receptors?

A

Via their own unique allosteric sites on the receptor.

46
Q

Name four symptoms that drugs that facilitate agonist-induced receptor activation may produce.

A

Sedation.
Anticonvulsant activity.
Muscle relaxation.
Anterograde amnesia.

47
Q

Benzodiazepines, barbiturates and steroids are positive allosteric modulators of GABAa receptors. How do they potentiate the actions of GABAa?

A

By shifting the dose-response curve to the left.

48
Q

How do benzodiazepines, barbiturates and steroids affect GABAa receptor channel opening?

A

Benzodiazepines = increase channel opening frequency.
Barbiturates = increase channel opening duration.
Steroids = increase channel opening frequency and duration.

49
Q

Are GABAb receptors ionotropic or metabotropic?

A

Metabotropic.

50
Q

Describe the structure of GABAb receptors.

A

7 transmembrane spanning domains.
Coupled to G-proteins and an array of second messenger systems.
Amino acid sequence homology of around 35%.

51
Q

GABAb receptors are the only GPCR currently known that functions as a what?

A

Heterodimer.

52
Q

How do subunits associate in GABAb receptors and what are the implications of this?

A

Associate via their C-terminal regions.
Via these interactions, B(R1) subunit can stimulate the B(R2) subunit to activate the G-protein.

53
Q

Why must the B(R1) and B(R2) subunits form a heterodimeric complex in order to function?

A

B(R1) binds to GABA, which B(R2) does not.
B(R2) is required to stimulate activation of the G-protein.

54
Q

Postsynaptic GABAb receptors couple to potassium channels. What does this lead to?

A

Hyperpolarisation.

55
Q

Presynaptic GABAb receptors couple to calcium channels. What does this lead to?

A

Decrease in calcium conductance.
Inhibition NT release.

56
Q

Describe the three ways in which postsynaptic GABAb receptors gate potassium channels.

A

They activate slow inhibitory postsynaptic potentials via activation of GIRKs.
They function as autoreceptors presynaptically via actions on voltage-gated calcium channels.
They negatively couple to adenylyl cyclase through which they influence downstream molecular signalling pathways.

57
Q

What are GIRKs?

A

G-protein coupled inwardly-rectifying potassium channels.

58
Q

Name the five possible roles of GABAb receptors.

A

Control of epilepsy.
Regulation of HPA axis.
Enhancement of antidepressant drug action.
Suppression of cocaine withdrawal symptoms.
Alleviation of pain.

59
Q

What does activation of GABAa and GABAb receptors under baseline conditions lead to?

A

Reduces postsynaptic depolarisation.
Prevents NMDAR conductance.

60
Q

How do GABAa and GABAb receptors interact during high frequency activation?

A

There is a decreased release of GABA due to the activation of presynaptic GABAb receptors.
This reduces postsynaptic GABAa activation.

61
Q

What does activation of GABAa and GABAb receptors during high frequency activation lead to?

A

Increases postsynaptic depolarisation.
Increases NMDAR conductance.
(This is one element of synaptic plasticity.)

62
Q

Is glycine an inhibitory or excitatory NT?

A

Inhibitory.

63
Q

What is the evidence that glycine acts as a co-agonist at NMDARs?

A

It potentiates the NMDA response in cultured mouse brain neurons.

64
Q

Which amino acid is involved in synthesising glycine from glucose?

A

Serine.

65
Q

Which enzyme is involved in synthesising glycine from serine?

A

Serine hyrdroxymethyltransferase (SHMT).

66
Q

What type of enzyme is SHMT?

A

Pyridoxal phosphate-dependent enzyme.

67
Q

Which vesicular transporter packages glycine into vesicles?

A

VIAAT (vesicular inhibitory amino acid transporter).

68
Q

How is glycine removed from the synaptic cleft?

A

By uptake transporters (GLYT1 and GLYT2) on astrocytes and presynaptic terminals.

69
Q

Where is GLYT1 expressed?

A

Astrocytes.
Neurons.

70
Q

Where is GLYT2 expressed?

A

Axons.
Presynaptic terminals.

71
Q

In which areas of the brain are GLTY1 and GLYT2 expressed?

A

Caudal areas.

72
Q

How and where is glycine degraded?

A

By glycine cleavage systems (GCS) in mitochondria.

73
Q

Some vesicles contain both glycine and GABA. Their co-release activates what?

A

Dedicated postsynaptic receptors.

74
Q

Why has it been suggested that other vesicular glycine transporters exist other than VIAATs?

A

In some areas of the CNS that are rich with GABA and/or glycine, the VIAAT is missing.

75
Q

Where are glycine receptors (GlyR) primarily found?

A

In the ventral spinal cord.

76
Q

What are the two roles of GlyR in the spinal cord?

A

Motor coordination.
Neuronal inhibition.

77
Q

How does strychnine act as a GlyR antagonist?

A

Upon binding, it prevents the opening of chloride channels.

78
Q

Which subunits is a GlyR typically comprised of?

A

3 alpha(1) and two beta subunits.

79
Q

How are GlyRs stabilised in the PSD and what is gephyrin’s role in this?

A

They are stabilised in the PSD by a subsynaptic scaffold.
Gephyrin acts as the core protein of the scaffold.

80
Q

Where is the gephyrin binding site found on GlyRs?

A

On the beta subunit.

Cellular Neuroscience (10 decks)

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