NEURO: Neurotransmitter Systems II: GABA and Glycine Flashcards
RECAP: what are the criteria for a neurotransmitter?
- the molecule must be synthesised and stored in the pre-synaptic neuron
- the molecule must be released by the pre-synaptic axon terminal upon stimulation
- the molecule must produce a response in the post-synaptic cell
What is the basis of the inhibitory mechanism?
The main aim of the inhibitory mechanism in cells is to hyperpolarise it (ie. to bring it further away from the threshold potential that will induce an action potential).
There are two ways in which ion channels can do this:
- when the ligand binds, it will allow negative ions (eg. Cl-) to flow in, decreasing the membrane potential
- when the ligand binds, it will allow K+ ions to flow out, thus decreasing the membrane potential
Thus, it could be due to an influx of negative charge, or an eflux of positive charge.
Describe GABA synthesis and storage.
GABA is synthesised from glutamate; this is done by the action of the enzyme glutamate decarboxylase (GAD) and pyridoxal phosphate (aka Vitamin B6, co-factor).
It is synthesised in the nerve terminals. Then, it is transported into vesicles by vesicular inhibitory amino acid transporters (VIAATs).
If we were to microscopically look at a nerve terminal/synapse, would we be able to distinguish vesicles holding glutamate or GABA/glycine?
Yes, because vesicles carrying glutamate tend to be more circular, while vesicles holding GABA/glycine tend to be more ovular.
The different vesicles shapes are just due to the electrostatic interactions of the different molecules in the vesicles able to make either circular or oval shapes.
Describe the GABA(A) receptor.
It is a ligand-gated Cl- channel. It sits in a pentameric structure.
There are six α subtypes (α1-α6), three β subtypes (β1-β3) and three γ subtypes (γ1-γ3). There are also some less commonly found subtypes such as δ, ε, π and θ.
The most common configuration is with 2 α, 2 β and a γ subunit.
The receptor is most commonly found post-synaptically.
There are multiple binding sites (on the receptor) for:
- agonists/antagonists (eg. GABA) [between α & β]
- benzodiazepines [between α & γ]
- channel modulators (eg. GA, alcohol)
- allosteric modulators (eg. barbiturates)
- channel blockers (eg. picrotoxin)
In what ways is GABA activity terminated?
- upon reuptake by GABA reuptake transporter GAT on the presynaptic membrane (GAT-1 in neurons, GAT-3 in glial cells)
- upon breakdown by GABA transaminase (GABA-T) –> succinic semialdehyde –> succinic acid by succinic semialdehyde dehydrogenase (SSADH)
- upon diffusion away from the synaptic cleft
Describe GABA(B) receptor.
It is a G protein-coupled receptor modulated by the αGi/o G protein cascade.
They exist as dimers, sometimes from two different subtypes (eg. GABA(B1) and GABA(B2))
It has two major effects:
- it opens potassium channels, causing the efflux of positive charge
- it blocks VGCCs, blocking the influx of positive charge
Thus, overall, it causes the hyperpolarisation of the cell.
How is GABA implicated in epilepsy?
GABA is very closely associated with epilepsy.
Epilepsy is a brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurons
By modulating how much GABA we have in the brain, we can produce the occurrence of seizures.
Epilepsy is a lot of excitation in the brain, so we can amp up the inhibition in different ways that could help us to level out the imbalance in excitation and inhibition.
List some different epilepsy drugs based on their mechanism of action.
GABA(A) RECEPTOR ENHANCERS:
- Barbiturates (not used anymore because of the risk of addiction and overdose)
- Benzodiazepines
- Progesterone
- Ganaloxone
GAT BLOCKERS:
- Tiagabine
GABA-TRANSAMINASE INHIBITOR:
- Vigabatrine
GAD MODULATORS?:
- Gabapentin
- Valproate
PRODRUG:
- Progabide (exogenous analogue of glutamate)
Describe glycine synthesis and storage.
Glycine is synthesised from 3-phosphoglycerate (a product in glycolysis). This gets converted to serine, which then gets converted to glycine by serine hydroxymethyl-transferase
It is synthesised in the nerve terminals, and it transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT).
Describe the glycine receptor.
It is a ligand-gated Cl- ion channel. It is found both pre- and post-synaptically. It has a pentameric structure.
It has 4 α subunit types (α1-4) and 1 β subunit type.
The most common configurations are 3α(1)2β or 4α(1)1β.
The agonist/antagonist binding sites and their requirements are unclear although plant alkaloid strychnine potently blocks glycine receptors.
What are the mechanisms of glycine activity termination?
- upon the reuptake of glycine by the high affinity Na+ dependent glycine reuptake transporter GlyTs - neurons: GlyT-2, glial cells (GlyT-1)
- upon break down by glycine decarboxylase
- upon glycine’s diffusion away from the synaptic cleft
How is glycine implicated with the NMDA receptor?
Glycine also plays a role in modulating the response of NMDA receptors.
Thus, it can increase inhibition (through its own mechanism), but also enhance excitation (due to NMDA receptor activation), making it a complex pharmacological target.
Describe how GABA is behind startle goats.
In startle goats, there is a decreased muscle chloride conductance – can be caused by glycine receptor mutations.
As the goats mature, GABAA receptors are upregulated to compensate.
What is hyperekplexia?
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).
