Lecture 3 - GABA

Question 1

How is GABA synthesised?

Answer 1

Synthesised from glutamate by the enzyme glutamate decarboxylase (throughout neuron by GAD67 and in nerve terminals by GAD65)

Question 2

How is GABA transported into cells?

Answer 2

GAT1 and GAT3 transporters

Question 3

How is GABA transported into vesicles?

Answer 3

VGAT transporters

Question 4

What is the structure of the GABAa receptor?

Answer 4

Ionotropic
Pentameric (5 subunits)
4 transmembrane domains, second one forms the ion channel 
N and C terminus both extracellular
N terminus has cys-cys loop

Question 5

What is the location and function of the GABAa receptor?

Answer 5

Postsynaptic only

Inhibitory as it allows chloride ion influx

Question 6

What are the positive allosteric modulators of the GABAa receptor?

Answer 6

Benzodiazepines
Alcohol
Barbiturates
Neurosteroids

Question 7

What is the subunit composition of the GABAa receptor?

Answer 7

Different compositions found in different parts of the brain

Most common is 2 alphas, 2 betas and a gamma or delta

Question 8

Where does GABA bind to the GABAa receptor?

Answer 8

At the alpha/beta subunit interface

Question 9

What is the structure of the GABAb receptor?

Answer 9

2 GPCRs (Obligate Dimer)
7 transmembrane domains
Extracellular N terminus
Intracellular C terminus 
GABAb-R1 and GABAb-R2

Question 10

Where does GABA bind to the GABAb receptor?

Answer 10

Binds to the GABAb-R1 receptor

GABAb-R2 interacts with the intracellular G proteins

Question 11

What is the location and function of the GABAb receptor?

Answer 11

Presynaptic and Postsynaptic
Inhibitory as coupled to Gi/o
Inhibits cAMP signalling
Inactivates presynaptic calcium channels, reducing neurotransmitter release
Activates postsynaptic GIRK channels, hyperpolarisation

Question 12

Name an agonist of the GABAb receptor

Answer 12

GABA, Baclofen

Question 13

Why don’t GABA receptors occur on dendritic spines?

Answer 13

Do not pass calcium therefore do not result in biochemical changes, only voltage changes

Question 14

What is the shape of the IPSP caused by GABA and why is it like this?

Answer 14

Biphasic
Caused by ionotropic and metabotropic receptor types
Initial dip caused by GABAa
Later, prolonged dip caused by GABAb

Question 15

What is the difference between wiring transmission and volume transmission?

Answer 15

Wiring transmission between compact, well-defined structures. Used by fast neurotransmitters. Localised responses
Volume transmission used by neuromodulators, diffuse to cover large areas

Question 16

Name an agonist, competitive antagonist and non-competitve antagonist of the GABAa receptor

Answer 16

Agonists = GABA, Muscimol
Competitive antagonists = Bicuculline, GABAzine
Non competitive antagonists = Picrotoxin, U93631

Question 17

Where do benzodiazepines bind to the GABAa receptor?

Answer 17

At the alpha-gamma subunit interface

Question 18

What do benzodiazepines do to the GABAa receptor and what physical effects does this have?

Answer 18

Increases frequency of channel openings
Anticonvulsant
Anti anxiety
Promotes sleep

Question 19

Name two BDZ-site inverse agonists and their uses

Answer 19

DMCM - Used to promote seizures

Flumazenil - used to treat BDZ overdoses

Question 20

How do barbiturates and neurosteroids act differently to BDZs?

Answer 20

Different binding site
At low concs are positive allosteric modulators, at high concs directly activate receptor
Increases duration of channel openings

Question 21

How do GABAb receptors modulate short term plasticity?

Answer 21

GABA released
Binds to presynaptic GABAb receptors (autoreceptors)
Inhibition of calcium channels
If a second action potential arrived in a short amount of time, less GABA is released

Question 22

What are the possible subunits for the GABAa receptor?

Answer 22

Alpha
Beta
Gamma 
Delta 
Phi