Neurotransmitter System II: Glutamate & Glycine Flashcards
What is GABA as a neurotransmitter?
- Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system
- First identified in the mammalian nervous system in 1950
- Around one third of synapses utilise GABA as a neurotransmitter
- It’s most commonly found as a inhibitory neurotransmitter in local circuit interneurons
How is GABA synthesised?
- Glutamate is converted to GABA via a glutamate decarboxylase enzyme. Uses pyridoxal phosphate
- Synthesised in the nerve terminals
- Transported into vesicles by vesicular inhibitory amino acid transporters
Describe the re-uptake of GABA
- Goes from the presynaptic terminal to the post synaptic neuron via GATS
- Neurons and glial contain high affinity Na+ dependent GABA reuptake transporters (GATS)
- Neurons = GAT-1
- Glial cells = GAT-
Describe the degradation of GABA
- GABA converted to succinic semialdehyde via the GABA trans animate enzyme (GABA-T)
- This is then converted to succinic acid via the succinic semialdehyde dehydrogenase enzyme (SSADH)
What are the two broad family of receptors?
- Ligand gated ion channels (ionotrophic)
- G protein coupled receptors (metabotropic)
What type of receptors does GABA bind to?
- Binds to both Ionotropic and metabotropic GABA receptors
- ionotropic receptors = GABAA (LGIC)
- Metabotropic receptors = GABAB (GPCR)
Describe the GABAB receptor
- G protein coupled receptor
- Has a Cysteine rich domain
- Has a 7 transmembrane domain
- Dimers: Heteromers GABAB1 and GABAB2
- Watch lecture for this bit
What can inhibitory neurotransmitters cause?
- Can cause neuronal membrane hyperpolarisation
- Which is the displacement of the membrane potential towards a more negative value
- Watch lecture
What is the cerebellum as a part of the brain?
- A prominent hind structure
- Accounts for approximately 10% of the human brains volume
What is the function of the cerebellum?
- Detects differences in Motor error between an intended movement and the actual movement
- Aids the motor cortex to produce precise and coordinated movement
- Doesn’t initiate movement
Is the function of the cerebellum conserved?
- Its been shown that the cerebellum is important in synchronisation of movement with musical rhythm
- This could be widespread across the animal kingdom
What are Purkinje cells?
A class of GABAergic neurons that comprise the principle projection neurons of the cerebellar cortex
Describe the structure of purkinje cells
Have elaborate dendritic trees that receive convergent input from cells in the molecular layer
What is the function of purkinje cells?
- They send GABAergic projections to deep cerebellar neurons
- Purkinje cell output to the deep cerebellar neurons which generates an error connection signal that can modify movements
- This provides the basis of real time control of precise and synchronous movement
How is GABA and glutamate balanced in the brain?
- GABA and glutamate are the major neurotransmitters in the brain
- Both work together to control the brains overall level of excitation
- In one step, the major neurotransmitter is converted into the other major neurotransmitter in the brain
How is Glutamate converted into GABA?
- Via a decarboxylase (GAD) enzyme which also contains pyridoxal phosphate
- GABA is then produced from Glutamate
What is Epilepsy?
A brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurons
How does epilepsy work?
GABAA receptor enhancers: Barbiturates Benzodiazepines
GAT blockers: Tiagabine
GABA transaminase inhibitor: Vigabatrine
GAD modulators: Gabapentin Valproate
Prodrug: Progabide
What is anxiety?
Can be defined as a feeling of unease (worry/fear) which can range from mild to severe
What is Glycine?
The second major inhibitory neurotransmitter in the central nervous system
How is glycine synthesised in the body?
3 phosphoglycerate (glycolysis) -> Serine -> glycine via serine hydroxymethyl transferase enzyme
Where is glycine synthesised?
In the nerve terminals
Where is the Glycine then transported to?
Transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT)
Describe the re-uptake of Glycine
- Goes from the presynaptic terminal to the post synaptic neuron via GlyT
- Neurons and glial contain high affinity Na+ dependent glycine re-uptake transporters (GlyTs)
- Glial cells = GlyT-1
- Neurons = GlyT-2
Describe the degradation of Glycine
Glycine is converted into Serine via the Serine hydroxymethyl-transferase enzyme
What type of receptor does glycine have?
Ligand gated Cl- channel
Describe the glycine receptor
- Ligand gated Cl- channel
- Has a pentameric structure containing 4 ã subtypes (ã1-ã4) and one β subtype
- 3α12β or 4α1β most common configuration
- Agonist/antagonist binding sites unclear – although plant alkaloid strychnine potently blocks glycine receptors
What is Hyperekplexia?
- A rare disorder characterised by hypertonic (increased muscle tone) and an exaggerated startle response
- Symptoms can manifest in relation to unexpected stimuli
What is the role of glycine in Hyperekplexia?
- Gene mutations can disrupt normal glycinergic neurotransmission
- Can lead to neuronal hyperexcitability
- Leads to hypertonia and exaggerated startle response
What happens in startle goats?
- There is descended muscle chloride conductance
- Can be caused by glycine receptor mutations
- As the goats mature, GABAA receptors are unregulated to compensate
