22- GABA

Question 1

what is GABA?

Answer 1

the major inhibitory neurotransmitter in the CNS

Question 2

describe the synthesis of GABA

Answer 2

synthesised in nerve terminals with glutamate as its precursor

glutamate, catalysed by GAD/ glutamate decarboxylase with pyridoxal phosphate as a co-factor, is decarboxylated into GABA

Question 3

what is pyridoxal phosphate derived from?

Answer 3

vitamin B6

Question 4

describe how GABA is stored

Answer 4

GABA is synthesised in nerve terminals and transported by VIAATs into synaptic vesicles for storage

vesicles have an oval appearance

VIAAT = vesicular inhibitory amino acid transporters

Question 5

describe GABA re-uptake - transporter(s) involved?

Answer 5

GABA re-uptake occur from the synapse into the pre-synaptic neurone allowing it to be recycled

re-uptake by GAT transporter which sit on the pre-synaptic terminal

neurones and glial cells have different isoforms of high-affinity Na+ dependent GABA reuptake GAT

neurones predominantly have GAT-1, glial cells have GAT-3. other isoforms are also present.

Question 6

describe the degradation of GABA

Answer 6

two step process involving two enzymes to terminate GABA activity

GABA broken down into succinic semialdehyde, catalysed by GABA transaminase

succinic semialdehyde broken down into succinic acid, catalysed by SSADH

Question 7

in what three ways can GABA activity be terminated at the synapse?

Answer 7

GABA can diffuse away from the synapse, re-uptake OR degradation

Question 8

what two enzymes are involved in GABA degradation?

Answer 8

GABA-T = GABA transaminase
SSADH = succinic semialdehyde dehydrogenase

Question 9

what is the name of the transporter responsible for GABA reuptake? how does it differ in neurones and glial cells?

Answer 9

GAT

different isoforms predominantly in neurones and glial cells. neurones = GAT-1; glial cells = GAT-3

Question 10

what enzyme and co-factor is involved in GABA synthesis?

Answer 10

enzyme = glutamate decarboxylase

co-factor = pyridoxal phosphate

Question 11

what are the two types of GABA receptor?

Answer 11

GABA-A ionotropic receptor (LG ion channel)
GABA-B metabotropic receptor (GCPR)

Question 12

how do GABA-A and B receptors work in inhibiting action potential firing?

Answer 12

GABA-A = GABA binds to receptor, ion channel core opens allowing Cl- influx

GABA-B = GABA binds to GCPR receptor, activates Gi/o G-protein which allows K+ efflux and interacts with Ca2+ ICs to prevent Ca2+ influx

both mechanisms result in hyperpolarisation where the membrane potential is more negative, inhibiting the generation and firing of an action potential

Question 13

structure of a GABA-A ionotropic receptor?

Answer 13

pentameric assembly of 5 subunits with a central ion channel core

can be made up of different subunit types - alpha, beta, gamma and others like epsilon and theta

most common configuration is 2 alpha, 2 beta and one gamma

Question 14

where are GABA-A receptors located?

Answer 14

on post-synaptic neurones

Question 15

structure of a GABA-B metabotropic receptor?

Answer 15

GCPR, 7 transmembrane domains, C terminal which allows two receptors to link together and form dimers

Question 16

describe GABA-A receptors as ideal drug targets

Answer 16

pentameric structure offers many binding sites, making it an attractive drug target

examples of drugs:
- agonists and antagonists = GABA binds between alpha and beta
- benzodiazepine = binds between alpha and gamma
- channel blockers and modulators = picrotoxin as a blocker
- allosteric modulators = barbiturates

Question 17

what are Purkinje cells?

Answer 17

GABAnergic principal projection neurons of the cerebellum

important in generating ‘error connection signals’ for motor control

Question 18

how do Purkinje cells contribute to cerebellar function?

Answer 18

cerebellum functions for precise and co-ordinated movement = detects ‘motor error’ between intended and actual movement

Purkinje cells are GABAnergic projection cells - dendritic trees receive convergent input from other motor regions and project to deep cerebellar regions

these projections allow for generating important ‘error connection signals’ = allow for modifying movements in real time

Question 19

why is the balance between GABA and glutamate important?

Answer 19

contributed to excitatory-inhibitory balance in the brain

helps control the overall excitation level in the brain

Question 20

what is epilepsy?

Answer 20

a brain disorder characterised by periodic, unpredictable seizures

mediated by excessive excitation in the brain, firing of neurons

Question 21

describe GABA-related treatments for epilepsy? why GABA?

Answer 21

GABA is an inhibitory neurotransmitter = drugs targeting the GABA system can be sued as antiepileptics

examples:
1. GABA-A receptor enhancers = allow Cl- influx and hyperpolarisation
2. GAD modulators = modulate enzyme involved in GABA synthesis from glutamate
3. GAT blockers = block transporter involved in GABA reuptake
4. GABA-transaminase inhibitor = inhibit enzyme involved in GABA degradation
5. prodrug = inactive drug that when metabolised in the body becomes pharmacologically active

Question 22

example of an antiepileptic prodrug?

Answer 22

progabide
- metabolised, increases GABA brain levels

Question 23

example of GAD modulators as antiepileptics?

Answer 23

gabapentin
valproate

Question 24

example of GABA-A receptor enhancers

Answer 24

benzodiazepines = binds at alpha-gamma binding site

barbiturates = binds to an allosteric site

Question 25

example of a GAT blocker?

Answer 25

tiagabine

Question 26

example of a GABA-transaminase inhibitor?

Answer 26

vigabatrine

Question 27

list 5 GABA-based antiepileptic drugs

Answer 27

GAT modulators
GABA-transaminase inhibitors
GAT blockers
GABA-A receptor modulators - benzodiazepines, barbiturates
prodrugs - e.g. progabide