4. GABA & GLYCINE Flashcards
(38 cards)
1
Q
What is GABA?
A
- GABA is the major inhibitory neurotransmitter found in the CNS
2
Q
How is GABA synthesised?
A
- GABA is synthesized from Glutamate in the nerve terminals
- Glutamate can be metabolised from glucose
- Glutamate –> GABA by Glutamate decarboxylase
3
Q
What enzyme is involved in GABA synthesis & what co-factor is needed?
A
- Glutamate -> GABA by GLUTAMATE DECARBOXYLLASE
- Pyridoxal phosphate is the co-factor for Glutamate decarboxylase. The co-factor is derived from Vitamin B6
4
Q
What is the transporter involved in transporting GABA into vesicles?
A
- GABA is transported into vesicles by VIAAT (Vesicular inhibitory amino acid transporter)
5
Q
What’s the difference between GABA & Glutamate storage in vesicles?
A
- GLUTAMATE = VGLUT & round vesicles
- GABA = VIAAT & oval vesicles
6
Q
What transporters are involved in re-uptake of GABA & what are the two types?
A
- GAT (GABA re-uptake transporters) take up GABA from the synaptic cleft into the pre-synaptic neurone.
- GAT are located on neurones & glial cells
1. GAT1 = neurones
2. GAT3 = glial cells
7
Q
What two enzymes are involved in the degradation of GABA?
A
- GABA is degraded by being converted to Succinic acid in two steps (two enzymes):
1. GABA-T (GABA Transaminase)
2. SSADH (Succinic Semi-aldehyde dehydrogenase) - GABA –> SUCCINIC SEMIALDEHYDE by GABA T
- SUCCINIC SEMIALDEHYDE –> SUCCINIC ACID by SSADH
8
Q
What are the two GABA receptors?
A
- GABA-A (IONOTROPIC/LIGR)
2. GABA-B 9METABOTROPIC/G-PROTEIN COUPLED)
9
Q
What are the properties of GABA A receptors?
A
- GABA A receptors are ligand gated Cl- ion channels
- Binding of GABA to the GABA A receptor results in a chloride efflux, leading to hyperpolarisation
- The hyperpolarisation of the membrane decreases the likelihood of action potential firing, as it increases the threshold for action potential firing
- Therefore it has an inhibitory effect
10
Q
What are the sub-units for GABA A receptor & the most common configuration?
A
- The GABA A receptor has five sub-units
- Most common: 2 alpha, 2 beta & one gamma
- There are several sub-types: 6 alpha sub-types, 3 beta & 3 gamma sub-types
- GABA binds at the interface between alpha & beta
11
Q
Where does GABA & other drugs bind on the GABA A receptor?
A
- The GABA A receptor has multiple binding sites making it a key drug target
- GABA = binds between alpha & gamma
- BENZODIAZEPINES = binds between alpha & gamma
- PICROTOXIN - non-competitive antagonist that blocks the GABA A ion channel
12
Q
What are the properties of the GABA B receptor?
A
- The GABA B receptor is a G-protein coupled receptor
- It is coupled to Gi/o so it’s negatively linked to adenylate cyclase resulting in decreased cAMP & therefore decreased Ca2+.
- The GABA B receptor has an inhibitory effect
13
Q
What are the two effects of the GABA B receptor & the consequence?
A
- Increase K+ efflux - G-protein signalling cascade activates potassium channels
- Decrease Ca2+ influx
- Both of these effects result in hyperpolarisation. reducing the likelihood of action potential firing
- Therefore, GABA B receptor has an inhibitory effect once activated
14
Q
Define hyperpolarisation?
A
- Hyperpolarisation refers to the displacement of teh membrane potential towards a more negative value.
- This means that more stimulation is needed to reach the threshold for depolarisation
15
Q
What is the cerebellum?
A
- The cerebellum is a prominent hindbrain structure that is involved in detecting differences between the intended movement and the actual movement.
- Help the motor cortex produce precise & controlled movement
16
Q
What are the Purkinje cells of the cerebellum?
A
- The Purkinje cells are the GABAergic projection of the cerebellum into the deep cerebellar cortex, which generates an error signal allowing movements to be modified
17
Q
What’s the importance of the GABA & Glutamate balance?
A
- Glutamate is the major excitatory neurotransmitter
- GABA is the major inhibitory neurotransmitter
- Disruptions in the excitatory-inhibitory balance can lead to disorders or anxiety, migraines etc.
18
Q
What are two disorders that occur as a result of disrupted inhibitory & excitatory balance?
A
- ANXIETY
- EPILEPSY
- A shift towards glutamatergic/excitatory neurotransmission can result in anxiety or epilepsy
19
Q
What is epilepsy?
A
- Epilepsy is a brain disorder characterized by periodic & unpredictable seizures. It involves rhythmic firing of large groups of neurones
- There’s too much glutamatergic neurotransmission, so it can be treated by increasing inhibitory neurotransmission or decreasing excitatory neurotransmission
20
Q
Give GABA-mediated treatments for epilepsy?
A
- GABA A enhancers - increase inhibitory neurotransmission
- GAT blockers - prevent re-uptake of GABA
- GAD MODULATORS - Increase activity of glutamate carboxylase which produces GABA from Glutamate
- GABA -T INHIBITORS - Prevent degradation of GABA
- PRODRUG - Administer a precursor of GABA which can be metabolised into GABA
21
Q
Give examples of GABA A receptor enhancers
A
GABA A enhancers - increase inhibitory neurotransmission, by increasing receptor activity to increase hyperpolarisation
E.g benzodiazepines & barbituates
22
Q
Give an example of GAT blockers?
A
- prevent re-uptake of GABA, to increase circulating GABA
- E.g Tiagabine
23
Q
Give an example of GAD Modulators
A
- E.g Gabapentin,Valproate
- Increase activity of glutamate carboxylase which produces GABA from Glutamate
24
Q
Give an example of a prodrug for GABA
A
- E.g Progabide
- Can be metabolised into GABA
25
Give an example of GABA-T inhibitors
- E.g Vigabatrine
| - Prevent degradation of GABA
26
Describe the basis by which anxiolytic treat anxiety
- Anxiety is caused by too much glutamatergic transmission, so it can be treated by increasing inhibitory neurotransmission
- GABA A receptor enhancers such benzodiazepines & barbituates are used
27
What is glycine?
- Glycine is the second major inhibitory neurotransmitter after GABA
- It is found mainly in the ventral horn
28
How is glycine synthesised?
- Glycine is synthesized from serine
- But serine is metabolised from 3 -phosphoglycerate from glycolysis
- Serine --> Glycine by SERINE HYDROXYMETHYTRANSFERASE
29
What enzyme is responsible for glycine synthesis?
- SERINE HYDROXYMETHYTRANSFERASE
| - It is involved in both the synthesis & degradation of glycine
30
Which transporters are involved in transporting glycine into vesicles?
- Glycine is stored in oval vesicles
| - It is packaged into vesicles by VIAAT (Vesicular Amino-acid transferase)
31
Which transporters are involved in the re-uptake of Glycine?
- Glycine is taken up from the synaptic cleft into teh pre-synaptic neurone by GlyT (Glycine re-uptake transporters)
- The GlyT are found on neurones & glial cells
- GlyT1 = glial cells
- GlyT2 = neurones
- Mutations in these transporters can lead to hypoglycaemia
32
How is glycine degraded?
- Glycine is converted to serine by SERINE HYDROXYMETHYLTRANSFERASE
33
What enzyme is involved in the synthesis & degradation of glycine?
- SERINE HYDROXYMETHYLTRANSFERASE
34
Describe the structure of the glycine receptor & the most common configuration
- The glycine receptor is a LIGR Cl- ion channel
- the glycine receptor is located on the post-synaptic & pre-synaptic membrane
- Glycine receptor has a pentameric structure
- It consists of 5 sub-units
- Most common: 3 alpha, 2 beta or 4 alpha, 1 beta
35
What's the effect of the glycine receptor?
- Glycine binding to the glycine receptor leads to an influx of chloride resulting in hyperpolarization
- The hyperpolaristaion decreases the likelihood of an action potential firing, resulting in an inhibitory effect
36
What other receptor can glycine bind to?
- Glycine can also bind to the NMDA receptor
| - Glycine can bind to the GLuN1 whilst glutamate binds to the GLuN2 subunit of the NMDA receptor
37
What is hyperekplexia & how does it occur?
- HYPEREKPLEXIA is characterised by hypermyotonia which is increased muscle tone leading to an exaggerated startled response
- Mutations can disrupt normal glycinergic neurotransmission. This leads to hyperexcitability due to the impaired glycinergic inhibition
38
What happens in myotonic goats?
- In myotonic goats there's decreased muscle chloride conductance. Normally a chloride influx causes hyperpolarisation, but glycine receptor mutation can affect whether this occur
- As the goats get older, their GABA A receptors will be upregulated to increase inhibition & to replace the impaired chloride conductance
