GABA and Glycine Flashcards
What do inhibitory neurotransmitters do?
They cause neuronal membrane hyperpolarisation (an action potential less likely to take place).
What is hyperpolarisation?
Displacement of a membrane potential towards a more negative value
What happens in a depolarisation?
At the resting potential, the membrane is -70mV. When there is sodium influx, the membrane potential becomes more positive - this is depolarisation.
What causes hyperpolarisation?
- Caused by the influx of negatively charged chloride ions in the cell.
- Potassium efflux causing positive ion out of the cell.
What is GABA?
Gamma-aminobutyric acid is the major inhibitory neurotransmitter in the CNS
How is GABA made?
It is synthesised from glutamate by the key enzyme glutamate decarboxylase (GAD), this requires a co-factor called pyridoxal phosphate derived from vitamin B6.
What is required for GAD to work?
Pyridoxal phosphate
Where does synthesis of GABA occur?
It occurs in the nerve terminals
What is the shape of glutamate and gaba vesicles and why is this important?
Glutamate is round
GABA is oval
To be able to distinguish them on a microscope image
How are GABA and Glycine transported into vesicles?
By vesicular inhibitory amino acid transporters
What type of channel is the GABAa receptor?
Ligand gated chloride channel
What is the structure of the GABAa receptor?
Six alpha subtypes (alpha 1 - alpha 6)
Three beta subtypes (Beta 1 - beta 3)
Three gamma subtypes (gamma 1 - gamma 3)
There is also other delta, zeta etc.
What is the most common structure of the GABAa receptor?
2alpha and 2 beta, gamma are the most common configuration
What activates GABAa receptors?
They are activated by GABA released from pre-synaptic neurons via synaptic vesicles
What causes the reuptake of GABA?
By the transporter called GABA reuptake transporter (GAT) which takes GABA back up into the pre-synaptic terminal. This will terminate GABA activity.
Where does GABA bind on the GABAa receptor?
Between the alpha and beta subunits
What else can bind to the GABAa receptor?
- Benzodiazepine binds between alpha and gamma subunits - used to treat anxiety and affects GABA neurotransmission
- Channel blockers e.g. Picrotoxin which prevents ion flow by blocking the channels
- Channel modulators e.g. GA (general anaesthetics)
- Allosteric modulators e.g. Barbiturates - also involved in anxiety treatment
What are GABAb receptors?
Metabotropic, G-coupled protein receptors
- Forms dimers which can be heteromers of GABAb1+2
- Coupled to a G protein - this is Gi/o.
- Activates potassium channels to facilitate potassium efflux which causes hyperpolarisation
- Block calcium influx into the cell to stop the chance of excitotoxicity
How is GABA reuptaken by neurons and glia?
Neurons and glial contain high-affinity Na+ dependent GABA re-uptake transporters (GAT).
Which GATs do neurons and glial cells have?
GAT-1 = neurons GAT-3 = glial cells
How is GABA degraded?
It is degraded by an enzyme called GABA transaminase (GABA-T). This forms succinic semialdehyde that is then degraded by an enzyme called succinic semialdehyde dehydrogenase (SSADH) into succinic acid.
What is the enzyme that degrades GABA into succinic semialdehyde?
GABA transaminase (GABA-T)
What is the enzyme that degrades succinic semialdehyde into succinic acid?
Succinic semialdehyde dehydrogenase (SSADH)
How are glutamate and GABA linked?
In one step, the major excitatory neurotransmitter, Glutamate is converted into the major inhibitory neurotransmitter, GABA. It is converted by glutamate decarboxylase (GAD) with the cofactor pyridoxal phosphate derived from vitamin B6.
What happens if there is a unbalance between GABA and glutamate?
This can cause failed neurotransmission such as epilepsy.
What is epilepsy?
A brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of a large group of neurons.
How is epilepsy treated?
By increasing the amount of inhibition, this allows GABA to be an important drug target for epilepsy.
What are the different types of drugs used to treatment epilespy? Give one example of each
GABAa receptor enhancers - barbiturates
GAT blockers - tiagabine
GABA-transaminase inhibitors - vigabatrine
GAD modulators - Gabapentin and Valproate
Prodrug - Progabide
Define a GABA prodrug
An inactive precursor of GABA which metabolises GABA in the body to serve its inhibitory function
Define Anxiety
It can be defined as a feeling of unease (e.g. worry or fear). It can range from mild to severe.
What is glycine and where is it found?
- Second major inhibitory neurotransmitter in the CNS
- Most commonly found as an inhibitory neurotransmitter in the ventral horn, the location for spinal interneuron terminals
- understanding is lagging behind GABA receptors in part due to limited allosteric modulators of the receptor.
Describe the synthesis of glycine
3-phosphoglycerate to serine then to glycine by the key enzyme serine hydroxymethyl-transferase.
Which enzyme is used to synthesis glycine?
serine hydroxymethyl-transferase
Where is glycine synthesised and how is it transported?
It is synthesised in the nerve terminals and transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT).
When was glycine’s presence in space confirmed?
It was confirmed in 2009 which supports the theory of panspermia.
What is panspermia?
The “building blocks” of life are widespread throughout the universe.
What type of receptor are glycine receptors?
Ligand gated Cl- receptor
Where are glycine receptors found?
They can be found post and pre-synaptically which differs from GABAa receptors which are just found post-synaptically.
What reuptakes glycine back into the neuron?
Once bound to the receptor and diffuse away, it is reuptaken into the neuron via GlyT.
What type of structure is the glycine receptor?
Pentameric Structure
- Four alpha strucutre
- One beta structure
- Most common is 3alpha, 2beta or 4alpha, 1 beta configuration
What are other molecules that bind to the glycine receptor?
- Agonist/antagonist binding sites are unclear
- Although, plant alkaloid strychnine potently blocks glycine receptors.
What other receptor does glycine activate?
Glycine also activates the glutamate receptor called NMDA.
Which type of NMDA receptors does glutamate and glycine bind to?
Glutamate binds to the GluN2 receptor.
Glycine/D-serine will bind to the GluN1 receptor to remove the magnesium block.
Which reuptake transporters are in the Glial cells and Neurons?
Glial cells = GlyT-1
Neurons = GlyT-2
What is Hyperekplexia?
A rare disorder characterised by hypertonia (increased muscle tone) and an exaggerated startle response.
What are the symptoms of hyperekplexia?
Symptoms can manifest in relation to unexpected stimuli e.g. loud noises
What is the role of glycine in hyperekplexia?
- Gene mutations (e.g. 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
What are hypertonic goats?
- There is decreased muscle chloride conductance caused by glycine receptor mutations
- As the goats mature, GABAa receptors are upregulated to compensate.
