Neuro: Neurotransmitter Systems II: GABA and Glycine Flashcards
1
Q
Give a brief description of GABA.
A
- The major inhibitory neurotransmitter in the central nervous system (CNS)
- Approximately one third of synapses utilise GABA as their principle neurotransmitter
- Most commonly found as an inhibitory neurotransmitter in local circuit interneurons
2
Q
Describe GABA synthesis and storage.
A
- GABA is synthesised in the nerve terminals
- Predominant precursor for GABA synthesis is glucose - metabolised to glutamate.
- The enzyme glutamate decarboxylase (GAD) and the co-factor pyridoxal phosphate (derived from vitamin B6) catalyses the conversion of glutamate to GABA.
- Absence of Vitamin B6 can lead to diminished GABA synthesis. This can result in seizures due to a lack of neuroinhibitory drive.
- Synthesised GABA is transported into synaptic vesicles by vesicular inhibitory amino acid transporters (VIAAT)
- Glutamate stored in rounded vesicles and GABA stored in more oval shaped vesicles.
3
Q
Describe GABA uptake and degradation.
A
- GABA is released by exocytosis and binds to post synaptic receptors. GABA’s activity needs to eventually be terminated.
- In terms of GABA re-uptake, neurones and glial cells contain high-affinity sodium ion dependant GABA re-uptake transporters (GAT). Neurones predominantly express GAT-1 and glial predominantly express GAT-3. Transport GABA from the synaptic cleft back into the neurone or glial cell for subsequent degradation.
- Two key enzymes are required for degradation. GABA transaminase (GABA-T) catalyses the conversion of GABA into succinic semialdehyde dehydrogenase (SSADH). SSADH catalyses the conversion of succinic semialdehyde succinic acid which is then metabolised.
4
Q
What receptors does GABA bind to?
A
- GABA binds at both ionotropic and metabotropic GABA receptors
- The ionotropic receptor is termed the GABAA receptor.
- The metabotropic receptor is termed the GABAB receptor.
- There is also an ionotropic GABAC receptor - this is similar to the GABAA receptor in terms of structure, function and mechanism of action. However it is insensitive to a number of drugs that act on the GABAA receptor.
5
Q
Describe the GABAA receptor.
A
- Ligand-gated ion channel receptor
- When GABA binds, there is influx of negatively charged chloride ions which can lead to hyper-polarisation. This inhibits action potential firing by increasing the stimulus required to fire an action potential.
- Pentameric - comprised of five subunits which form the ion channel in various combinations
- There are 6 alpha subtypes, 3 beta subtypes, 3 gamma subtypes, as well as several other subunits.
- The most common configuration for a GABAA receptor is two alpha, two beta and a gamma subunit. GABA binds between the interface of the alpha and beta subunits of the receptor.
- Predominantly post-synaptic.
- Key drug target due to a number of different binding sites present on the receptor
6
Q
What are the key drug targets on the GABAA receptor?
A
- Agonists/antagonists e.g. GABA
- Benzodiazepine binding site
- Channel blockers e.g. picrotoxin
- Channel modulators e.g. GA
- Allosteric modulators e.g. barbiturates
- Benzodiazepines bind between the alpha and gamma subunits of the receptor
- Picrotoxin is a poisonous toxin that acts as a central nervous system stimulus. Non-competitive antagonist which functions to block the GABAA receptor ion pore and therefore GABA neurotransmission
- General anaesthetics (GA) can act as GABAA channel modulators and serve to increase GABAA receptor opening
- Barbiturates can also bind to the receptor - once used as drugs for anxiety and insomnia but are no longer recommended for this purpose and are used in epilepsy
7
Q
Describe the GABAB receptor.
A
- Metabotropic receptor
- Assemble as heteromers. Comprised of a GABAB1 and GABAB2 subunit.
- Neurotransmitter binding activates the G protein Gi/o which dissociates from the GABAB receptor. The G protein activates a secondary messenger pathway, inhibiting an enzyme called adenylyl cyclase which reduces levels of the secondary messenger cAMP. This leads to the activation of potassium channels. Activation of potassium channels leads to efflux of potassium ions out of the cell. Inhibitory effects are also mediated by blocking voltage gated calcium channels which is crucial for the action potential. This causes hyper-polarisation.
8
Q
How can inhibitory neurotransmitters e.g. GABA cause displacement of a membrane potential?
A
Inhibitory neurotransmitters (e.g. GABA) can cause neuronal membrane hyperpolarisation.
- This hyper-polarisation occurs via a influx of negatively charged chloride ions and via the efflux of positively charged potassium ions.
9
Q
What happens when there is stimulation of a GABAergic interneuron?
A
- Transient inhibition of action potential firing in its post synaptic target
10
Q
Describe the cerebellum.
A
- Prominent hindbrain structure and accounts for approximately 10% of the human brains volume.
- The cerebellum does not initiate movement but detects differences in “motor error” between an intended movement and the actual movement
- Aids the motor cortex to produces precise and co-ordinated movement
- Cerebellum is important in synchronisation of movement with musical rhythm
11
Q
Describe the GABA projections in the cerebellum.
A
- Called Purkinie cells (class of GABAergic neurons that comprise the principle projection neurons of the cerebellar cortex)
- Purkinjie cells have elaborate dendritic trees that receive convergent synaptic input from cells in the molecular layer.
- Purkinjie cells send GABAergic projections to deep cerebellar neurones.
- Purkinje cells output to the deep cerebellar neurons which generates an error connection signal that can modify movements
- This provides the basis for real-time control of both precise and synchronous movement
12
Q
Describe the balance of GABA and glutamate.
A
- GABA is the major inhibitory neurotransmitter and glutamate is the major excitatory neurotransmitter in the brain - both work together to control the brain’s overall level of excitation.
- Precursor for GABA synthesis is glutamate. Glutamate converted to GABA via the action of glutamate decarboxylase (GAD)
- Balance between GABA and glutamate needs to be tightly regulated for normal brain function.
13
Q
What can happen if this excitatory-inhibitory balance of GABA and glutamate is disrupted?
A
- Epilepsy - seizures mediated by rhythmic firing of large groups of neurons. Too much glutamatergic excitation.
- Anxiety
14
Q
How can you restore the excitatory-inhibitory balance of GABA and glutamate if it is disrupted (epilepsy)?
A
- If there is too much glutamatergic excitation, you need increased GABAergic inhibition
- GABAA receptor enhancers such as the barbiturates and benzodiazepines increase GABAergic neurotransmission by acting as positive allosteric
modulators at the GABAA receptor. - GABA re-uptake transporters (GAT blockers) blockers block re-uptake of GABA into presynaptic neurone so increase availability of GABA in the synaptic cleft
- GABA-transaminase inhibitors. This inhibition will increase the availability of GABA since this is the enzyme that catalyses the breakdown of GABA
- Glutamate decarboxylase (GAD) modulators such as gabapentin and valproate increase the activity of the enzyme GAD in order to increase the conversion of glutamate to GABA.
- Prodrugs which are inactive precursors such as progabide can be metabolised by the body into GABA
- Also other anti-epileptic drugs which can directly decrease excitation as opposed to ones that target GABA neurotransmission.
15
Q
How can you restore the excitatory-inhibitory balance of GABA and glutamate if it is disrupted (anxiety)?
A
There are anxiolytics such as the benzodiazepines - these act as positive allosteric modulators at the GABAA receptor in order to increase GABAergic neurotransmission
