Neurotransmitter Systems I: GABA and Glycine Flashcards
What is GABA?
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS).
Approximately one third of synapses utilise GABA as their neurotransmitter
GABA most commonly found as an inhibitory neurotransmitter in local circuit interneurons
How is GABA synthesised and stored?
Glucose is metabolised to glutamate
The enzyme glutamate decarboxylase (GAD) along with the cofactor pyridoxal phosphate (derived from vitamin B6) catalyses the conversion of glutamate to GABA
GAD catalyses the decarboxylation of GABA
Synthesised in the nerve terminals
Once synthesised GABA is transported into synaptic vesicles by vesicular inhibitory amino acid transporters (VIAAT)
Glutamate tends to be stored in round vesicles whereas GABA tends to be stored in oval vesicles
How is GABA re-uptaken and degraded?
Re-uptake:
Both neurons and glial cells contain high affinity Na+ dependent GABA reuptake transporters (GAT)
Neurons express mostly GAT-1 while glial cells express GAT-3, both take GABA from the synaptic cleft into the neuron or glial cells for degradation
Degradation:
GABA transaminase (GABA-T) catalyses the conversion of GABA to succinic semialdehyde
Succinic semialdehyde dehydrogenase (SSADH) catalyses the conversion of succinic semialdehyde to succinic acid
What types of receptors does GABA bind to?
GABA binds at both ionotropic and metabotropic GABA receptors.
The ionotropic is termed the GABAA receptor
The metabotropic is termed the GABAB receptor
There is also a GABAC receptor that is ionotropic but is insensitive to many drugs
What happens when GABA binds to the GABA A receptor?
Upon binding to the ionotropic receptor a influx of Cl- ions is let through
This can lead to hyperpolarisation which inhibits action potential firing
Pentameric structure composed of varying subtypes, there are:
6 alpha, 3 beta, 3 gamma and also a couple others
The most common configuration is 2 alpha 2 beta 1 gamma
Predominantly post synaptic location
Multiple binding sites:
- Agonists/antagonists e.g. GABA between alpha and beta
- Benzodiazepine binding site between alpha and gamma
- Channel blockers e.g. picrotoxin blocked the pore
- Channel modulators e.g. GA. Increase GABAA receptor opening
- Allosteric modulators e.g. barbiturates bind to receptor
What is the GABAB receptor like?
Comprise a large extracellular domain for neurotransmitter binding
A characteristic 7-transmembrane domain structure
And an intracellular C-terminal domain
GABAB receptors form as heteromers comprised of GABAB1 and GABAB2 subunits
Neurotransmitter binding activates the Gi/o protein which dissociates from the GABAB receptor
The G protein activates a secondary messenger pathway inhibiting an enzyme called adenylate cyclase which decreases levels of the secondary messenger cAMP
This leads to the activation of potassium channels leading to an efflux of potassium ions out of the cell
In addition these inhibitory effects also work by blocking voltage-gated calcium channels
Together this serves to cause hyperpolarisation
What is the cerebellum and its functions?
The cerebellum (or “little brain”) is a prominent hindbrain structure – it accounts for approximately 10% of the human brains volume. Cerebellum function - 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 coordinated movement Is the function of the cerebellum conserved?: It has been shown that, for example, the cerebellum is important in synchronisation of movement with musical rhythm This may be widespread across the animal kingdom…
What are Purkinje cells and what do they do?
Purkinje cells are a class of GABAergic neurons that comprise the principle projection neurons of the cerebellar cortex.
Purkinje cells have elaborate dendritic trees that receive convergent input from cells in the molecular layer
Purkinje cells send GABAergic projections to deep cerebellar neurons
Purkinje cell output to the deep cerebellar neurons generates an error connection signal that can modify movements
This provides the basis for real-time control of precise and synchronous movement
What is epilepsy?
Epilepsy is a brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurons.
Too much excitation? -> we can sue drugs to increase inhibition*
*Other anti-epileptics directly decrease excitation
What is glycine?
Glycine is the second major inhibitory neurotransmitter in the central nervous system (CNS).
Glycine most commonly found as an inhibitory neurotransmitter in the ventral horn of the spinal cord, the location for spinal interneuron terminals
However, our understanding of the glycine receptor is lagging behind the GABA receptors – in part due to limited allosteric modulators of the receptor
How is glycine synthesised and stored?
Glycine is synthesised from serine via the mitochondrial isoform of the enzyme serine hydroxymethyl-transferase
Synthesised in the nerve terminals
Transported to vesicles via VIAAT
Both GABA and glycine are stored in oval vesicles
How is glycine re-uptake and degraded?
Re-uptake:
It is taken up by high affinity Na+ dependent glycine re-uptake transporters (GlyTs)
Glial cells tend to have GlyT-1 and neurons GlyT-2
Mutations in these can lead to hyperglycinaemia resulting in lethargy and seizures
Degradation:
Various enzymes are responsible for the breakdown of glycine- including the reversal of glycine biosynthesis through the action of serine hydroxymethyl-transferase
What is the glycine receptor like?
Once bound to the ligand gated channel this brings in an influx of Cl- ions which causes hyperpolarisation
Pentameric structure
There are four alpha subtypes and one beta subtype with the most common configuration being 3a and 2b or 4a and 1b
Agonist and antagonist binding sites are unclear- although plant alkaloid strychnine potently blocks glycine receptors
Glycine receptor is both pre-synaptic and post-synaptic
Glycine can also act as a co-agonist in an NMDA receptor along with glutamate
What is hyperekplexia and what does glycine have to do with it?
Hyperekplexia is a rare disorder characterised by hypertonia (increased muscle tone) and an exaggerated startle response.
Symptoms can manifest in relation to unexpected stimuli (e.g. loud noises)
What is the role of glycine here?:
- Gene mutations (e.g. in glycine receptors, glycine transporters) can disrupt normal glycinergic neurotransmission
- Can lead to neuronal hyperexcitability (by impairing glycinergic inhibition)
- Leads to hypertonia and exaggerated startle response
