Neurotransmitter systems II: GABA and Glycine Flashcards
What are the Inhibitory Neurotransmitters?
GABA and glycine
Whatdo inhibitory neurotransmitters do?
hyperpolarise the postsynaptic cell, meaning an action potential is less likely to take place
What are the main mechanisms which cause hyperpolarisation?
2 main mechanisms which cause hyperpolarisation:
- influx of negatively charged Cl- ions
- efflux of positively charged K+ ions
What is the major inhibitory neurotransmitter in the CNS?
GABA (gamma-aminobutyric acid)
Describe GABA synthesis.
Glutamate (excitatory) converted to GABA (inhibitory) in the nerve terminals via the action of glutamate decarboxylase (GAD) using a cofactor called pyridoxal phosphate (derived from vitamin B6)
Describe GABA storage.
GABA transported into synaptic vesicles by vesicular inhibitory amino acid transporters (VIAAT)
What is the Difference in shape between glutamate and GABA synaptic vesicles?
glutamate vesicles are more rounded, whereas GABA vesicles are more oval shaped
Describe the structure of the GABAa receptor.
ionotropic 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
Describe the Stimulation of GABAa receptor.
GABA binds receptor
Cl- channel opens
Cl- influx
Hyperpolarisation
What is the Most common GABAa configuration?
2alpha
2beta
gamma
Where are GABAa receptors located?
post-synaptically
Describe the GABAa receptor binding sites.
The GABAa receptor has multiple binding sites:
· Agonists/Antagonists (e.g. GABA): binds between alpha and beta subunits
· Benzodiazepine binding site: binds between alpha and gamma subunits
· Channel blockers (e.g. picrotoxin): block the channel and prevent ion flow
· Channel modulators (e.g. GA)
· Allosteric modulators (e.g. barbiturates)
*because GABAa has multiple binding sites, it makes an attractive drug target for multiple disorders (e.g. epilepsy)
Describe the process of GABA reuptake?
After GABA has been released into synaptic cleft and binds GABA receptors on post-synaptic membrane, GABA is reuptaken by the presynaptic terminal via the GABA reuptake transporter (GAT)
neurones and glial contain high-affinity Na+ dependent GABA reuptake transporters (GATs):
- neurones contain GAT-1
- glial cells contain GAT-3
Describe the process of Stimulation of GABAb receptor.
GABA binds GABAb receptor (Gi/o) causing hypoerpolarisation by:
- activating K+ channels to facilitate K+ efflux
- blocking Ca2+ influx into the cell
Describe the structure of the GABAb receptor.
metabotropic G-protein coupled receptor (Gi/o):
· Extracellular Venus Flytrap Domain: for ligand binding
· 7 Transmembrane Domains
· Intracellular C-terminal Domain: coupled to a G-protein (Gi/o)
forms dimers:
-heteromers: GABAb1 & GABAb2
Describe the process of 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)
What is epilepsy?
brain disorder characterised by periodic and unpredictable seizures mediated by the rhythmic firing of large groups of neurones
-TOO MUCH EXCITATION
How is epilepsy targeted?
Increase the amount of GABA mediated inhibition to decrease excitation
What is Anxiety?
feeling of unease (e.g. worry or fear) which can range from mild to severe
-can be normal or pathological
What is the second major inhibitory neurotransmitter in the CNS?
Glycine
Where is glycine most commonly found?
in the ventral horn
Describe the process of Glycine Synthesis.
Via Glycolysis:
-serine converted to glycine in nerve terminals by enzyme Serine hydroxymethyl-transferase
Describe the process of Glycine storage.
glycine transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT), like GABA
What is a Glycine receptor.
ionotropic ligand gated Cl- channel
>binding of glycine will lead to opening of the channel and an influx of Cl- ions, causing hyperpolarisation
Describe the Glycine receptor structure.
pentameric structure with:
- Four ⍺ subtypes (⍺1-⍺4)
- One β subtypes
- most common configuration is:
- 3⍺, 2β
- 4⍺, 2β
What is known about Glycine binding sites?
agonist/antagonist binding sites are unclear
What is the function of Glycine receptor modulators?
modulators of this receptor lag behind the GABA receptor, although there is one known modulator:
· Strychnine- plant alkaloid which potently blocks the glycine receptors
Where are glycine receptors found?
pre-synaptically and post-synaptically
Describe the process of Glycine reuptake.
Neurones and glial cells contain high-affinity Na+ dependent glycine re-uptake transporters (GlyTs)
· Glial cells: GlyT-1
· Neurones: GlyT-2
Describe the process of Glycine degradation.
Glycine converted back to serine by Serine hydroxymethyl-transferase
What is Hyperekplexia?
rare disorder characterised by hypertonia (increased muscle tone) and an exaggerated startle response
Other than glycine receptors, what other receptors can glycine stimulate?
NMDA receptors:
- Glutamate binds to the GluN2 subunits
- Glycine or D-serine binds to the GluN1 subunit
What causes hyperekplexia?
Gene mutations (e.g. glycine receptors or transporters) disrupt normal inhibitory glycinergic neurotransmission, leading to neuronal hyperexcitability due to impaired glycingergic inhibition
Describe Hyperekplexia in goats.
In startle (or myotonic/fainting) goats, there is a decrease muscle chloride conductance- can be caused by glycine receptor mutations.
As the goats mature, GABAa receptors (ligand gated Cl- channels) are upregulated to compensate glycine receptor mutations/deficiency.
