GABA and Glycine

Question 1

What type of NT is GABA?

Answer 1

Amino acid.

Question 2

What type of NT is glycine?

Answer 2

Amino acid.

Question 3

How is GABA synthesised?

Answer 3

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

Question 4

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

Answer 4

GAD is only found in neurons that synthesise GABA.

Question 5

Where in the brain is GABA located?

Answer 5

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

Question 6

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

Answer 6

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

Question 7

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

Answer 7

It pumps GABA back into vesicles in the GABAergic terminals.

Question 8

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

Answer 8

It degrades GABA into succinic semialdehyde (SSA).

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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

Question 11

How is GABAc pharmacologically distinct from GABAa?

Answer 11

Classic GABAa agonists, e.g. isoguvacine, have no effect on GABAc.

Question 12

Why might GABAc just be a variant of GABAa?

Answer 12

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

Question 13

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

Answer 13

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

Question 14

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

Answer 14

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

Question 15

Which GABA receptor(s) are ionotropic?

Answer 15

GABAa and GABAc.

Question 16

Which GABA receptor(s) are metabotropic?

Answer 16

GABAb.

Question 17

Are GABA receptors located presynaptically or postsynaptically?

Answer 17

Both.

Question 18

How do GABAb receptors cause presynaptic inhibition?

Answer 18

They suppress calcium influx and reduce NT release.

Question 19

How do GABAb receptors cause postsynaptic inhibition?

Answer 19

They activate potassium currents that hyperpolarise the cell.

Question 20

How do GABAa receptors cause inhibition?

Answer 20

The inward chloride currents that go through GABAa receptors contribute to membrane inhibition via IPSCs.

Question 21

Describe the composition of GABAa receptors.

Answer 21

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

Question 22

How many subunits and subunit families do GABAa receptors have?

Answer 22

19 different subunits in 8 families.

Question 23

Which is the most prevalent GABAa subunit?

Answer 23

Alpha-1 (a1).

Question 24

Which is the most prevalent GABAa subtype?

Answer 24

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

Question 25

Where is the a2 GABAa subunit most abundant?

Answer 25

Regions where a1 is absent.

Question 26

Where is the a3 subunit expressed?

Answer 26

Regions complementary to a1.

Question 27

Where is the a6 subunit expressed?

Answer 27

Almost exclusively in the cerebellum.

Question 28

Why do receptors have different subunit compositions?

Answer 28

To have different functional characteristics.

Question 29

What is the function of alpha GABAa subunits?

Answer 29

Recognition of benzodiazepines.

Question 30

What is the function of beta GABAa subunits?

Answer 30

Recognition of GABA (endogenous agonist).

Question 31

What is the function of gamma GABAa subunits?

Answer 31

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

Question 32

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

Answer 32

Chloride ions.

Question 33

What does GABAa activation produce at inhibitory synapses?

Answer 33

IPSP (inhibitory postsynaptic potential).

Question 34

What are the two agonists of GABAa receptors?

Answer 34

GABA. Muscimol.

Question 35

What is the antagonist of GABAa receptors?

Answer 35

Bicuculline.

Question 36

What is the channel blocker for GABAa receptors?

Answer 36

Picrotoxin.

Question 37

Name all 8 subunit families for GABAa.

Answer 37

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

Question 38

Which GABAa subunits can form heteromeric complexes?

Answer 38

Alpha, beta, gamma, delta and epsilon.

Question 39

Where in the body is the pi-subfamily expressed?

Answer 39

Reproductive organs.

Question 40

Where do inhibitory interneurons often make axosomatic synpases?

Answer 40

Close to the axon hillock.

Question 41

How can IPSPs attenuate the excitatory effects of EPSPs?

Answer 41

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

Question 42

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

Answer 42

Benzodiazepines. Barbiturates. Neurosteroids. General anaesthetics.

Question 43

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

Answer 43

By shifting the dose-response curve to the left.

Question 44

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

Answer 44

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

Question 45

Are GABAb receptors ionotropic or metabotropic?

Answer 45

Metabotropic.

Question 46

Describe the structure of GABAb receptors.

Answer 46

7 transmembrane spanning domains. Coupled to G-proteins and an array of second messenger systems.

Question 47

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

Answer 47

Heterodimer.

Question 48

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

Answer 48

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

Question 49

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

Answer 49

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

Question 50

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

Answer 50

Hyperpolarisation.

Question 51

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

Answer 51

Decrease in calcium conductance. Inhibition NT release.

Question 52

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

Answer 52

They activate slow IPSPs 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.

Question 53

What are GIRKs?

Answer 53

G-protein coupled inwardly-rectifying potassium channels.

Question 54

Name the five possible roles of GABAb receptors.

Answer 54

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

Question 55

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

Answer 55

Reduces postsynaptic depolarisation. Prevents NMDAR conductance.

Question 56

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

Answer 56

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

Question 57

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

Answer 57

Increases postsynaptic depolarisation. Increases NMDAR conductance.

Question 58

Is glycine an inhibitory or excitatory NT?

Answer 58

Inhibitory.

Question 59

Which amino acid is involved in synthesising glycine from glucose?

Answer 59

Serine.

Question 60

Which enzyme is involved in synthesising glycine from serine?

Answer 60

Serine hyrdroxymethyltransferase (SHMT).

Question 61

Which vesicular transporter packages glycine into vesicles?

Answer 61

VIAAT (vesicular inhibitory amino acid transporter).

Question 62

How is glycine removed from the synaptic cleft?

Answer 62

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

Question 63

Where is GLYT1 expressed?

Answer 63

Astrocytes. Neurons.

Question 64

Where is GLYT2 expressed?

Answer 64

Axons. Presynaptic terminals.

Question 65

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

Answer 65

Caudal areas.

Question 66

How and where is glycine degraded?

Answer 66

By glycine cleavage systems (GCS) in mitochondria.

Question 67

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

Answer 67

Dedicated postsynaptic receptors.

Question 68

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

Answer 68

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

Question 69

Where are glycine receptors (GlyR) primarily found?

Answer 69

In the ventral spinal cord.

Question 70

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

Answer 70

Motor coordination. Neuronal inhibition.

Question 71

How does strychnine act as a GlyR antagonist?

Answer 71

Upon binding, it prevents the opening of chloride channels.

Question 72

Which subunits is a GlyR typically comprised of?

Answer 72

3 alpha(1) and two beta subunits.

Question 73

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

Answer 73

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

Question 74

Where is the gephyrin binding site found on GlyRs?

Answer 74

On the beta subunit.