NEURO: Neurotransmitter Systems II: GABA and Glycine Flashcards
Give examples of Inhibitory Neurotransmitters and what they do?
GABA (gamma-aminobutyric acid) and glycine
hyperpolarise the postsynaptic cell, meaning an action potential is less likely to take place ( (ie. to bring it further away from the threshold potential that will induce an action potential).
What are the main mechanisms which cause hyperpolarisation?
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
Describe GABA synthesis and storage.
Glutamate (excitatory) converted to GABA (inhibitory) in via the action of glutamate decarboxylase (GAD) using a cofactor called pyridoxal phosphate (derived from vitamin B6)
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?
glutamate vesicles are more rounded, whereas GABA vesicles are more oval-shaped
The different vesicle shapes are due to the electrostatic interactions of the different molecules in the vesicles
Describe the GABA(A) receptor.
Most common GABAa configuration
ligand-gated Cl- channel
pentameric, consisting of 5 subunits, and each of the subunits has different subtypes:
- Six ⍺ subtypes (⍺1-⍺6)
- Three β subtypes (β1-β3)
- Three 𝛾 subtypes ( 𝛾1-𝛾3)
- Also ẟ,ε, pi, theta subunits is a ligand-gated Cl- channel. It sits in a pentameric structure.
The most common configuration is with 2 α, 2 β and a γ subunit.
The receptor is most commonly found post-synaptically.
GABAa receptor binding sites
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)
*because GABAa has multiple binding sites, it makes an attractive drug target for multiple disorders (e.g. epilepsy)
Stimulation of GABAa receptor
GABA binds receptor
Cl- channel opens
Cl- influx
Hyperpolarisation
In what ways is GABA activity terminated?
- upon reuptake by GABA reuptake transporter (GAT) on the presynaptic membrane
- upon breakdown by GABA transaminase
- upon diffusion away from the synaptic cleft
Describe GABA(B) receptor structure
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))
· Extracellular Venus Flytrap Domain: for ligand binding
· 7 Transmembrane Domains
· Intracellular C-terminal Domain: coupled to a G-protein (Gi/o)
Stimulation of GABAb receptor
GABA binds GABAb receptor (Gi/o) causing hyperpolarisation by:
- activating K+ channels to facilitate K+ efflux
- blocking Ca2+ influx into the cell
GABA Reuptake
neurones and glial contain high-affinity Na+ dependent GABA reuptake transporters (GATs):
- neurones contain GAT-1
- glial cells contain GAT-3
GABA Degradation
1) GABA is degraded via an enzyme called GABA transaminase (GABA-T) into a compound called Succinic semialdehyde.
2) Succinic semialdehyde then converted into Succinic acid via an enzyme called Succinic semialdehyde dehydrogenase (SSADH)
How is GABA implicated in epilepsy?
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.
What is epilepsy?
a brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurones
-TOO MUCH EXCITATION
Targeting Epilepsy
Increase the amount of GABA mediated inhibition to decrease excitation