4. GABA & GLYCINE Flashcards
What is GABA?
- GABA is the major inhibitory neurotransmitter found in the CNS
How is GABA synthesised?
- GABA is synthesized from Glutamate in the nerve terminals
- Glutamate can be metabolised from glucose
- Glutamate –> GABA by Glutamate decarboxylase
What enzyme is involved in GABA synthesis & what co-factor is needed?
- Glutamate -> GABA by GLUTAMATE DECARBOXYLLASE
- Pyridoxal phosphate is the co-factor for Glutamate decarboxylase. The co-factor is derived from Vitamin B6
What is the transporter involved in transporting GABA into vesicles?
- GABA is transported into vesicles by VIAAT (Vesicular inhibitory amino acid transporter)
What’s the difference between GABA & Glutamate storage in vesicles?
- GLUTAMATE = VGLUT & round vesicles
- GABA = VIAAT & oval vesicles
What transporters are involved in re-uptake of GABA & what are the two types?
- 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
What two enzymes are involved in the degradation of GABA?
- 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
What are the two GABA receptors?
- GABA-A (IONOTROPIC/LIGR)
2. GABA-B 9METABOTROPIC/G-PROTEIN COUPLED)
What are the properties of GABA A receptors?
- 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
What are the sub-units for GABA A receptor & the most common configuration?
- 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
Where does GABA & other drugs bind on the GABA A receptor?
- 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
What are the properties of the GABA B receptor?
- 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
What are the two effects of the GABA B receptor & the consequence?
- 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
Define hyperpolarisation?
- 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
What is the cerebellum?
- 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
What are the Purkinje cells of the cerebellum?
- 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
What’s the importance of the GABA & Glutamate balance?
- 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.
What are two disorders that occur as a result of disrupted inhibitory & excitatory balance?
- ANXIETY
- EPILEPSY
- A shift towards glutamatergic/excitatory neurotransmission can result in anxiety or epilepsy
What is epilepsy?
- 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
Give GABA-mediated treatments for epilepsy?
- 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
Give examples of GABA A receptor enhancers
GABA A enhancers - increase inhibitory neurotransmission, by increasing receptor activity to increase hyperpolarisation
E.g benzodiazepines & barbituates
Give an example of GAT blockers?
- prevent re-uptake of GABA, to increase circulating GABA
- E.g Tiagabine
Give an example of GAD Modulators
- E.g Gabapentin,Valproate
- Increase activity of glutamate carboxylase which produces GABA from Glutamate
Give an example of a prodrug for GABA
- E.g Progabide
- Can be metabolised into GABA
Give an example of GABA-T inhibitors
- E.g Vigabatrine
- Prevent degradation of GABA
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
What is glycine?
- Glycine is the second major inhibitory neurotransmitter after GABA
- It is found mainly in the ventral horn
How is glycine synthesised?
- Glycine is synthesized from serine
- But serine is metabolised from 3 -phosphoglycerate from glycolysis
- Serine –> Glycine by SERINE HYDROXYMETHYTRANSFERASE
What enzyme is responsible for glycine synthesis?
- SERINE HYDROXYMETHYTRANSFERASE
- It is involved in both the synthesis & degradation of glycine
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)
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
How is glycine degraded?
- Glycine is converted to serine by SERINE HYDROXYMETHYLTRANSFERASE
What enzyme is involved in the synthesis & degradation of glycine?
- SERINE HYDROXYMETHYLTRANSFERASE
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
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
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
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
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
