GABA-A receptor electrophysiology Flashcards
Name the channels associated with epilepsy and migrains?
Sodium
potassium
calcium
GABAA
Nicotinic
Name the channels associated with neuromuscular disorders?
Sodium
Potassium
Calcium
Chlorine
Nicotinic
Name the channels associated with cerebellar ataxia and excessive startle?
Potassium
Calcium
Glycine
Name the 5 ligands assocaited with Cys-loop receptors?
- ACh
- 5-HT (serotonin)
- Zn
- GABA
- Glycine
Cys loop receptors characteristics?
Pentameric
Ligand-gated
Ion channel
Name the two types of cysteine-loop receptors?
- Cation (positively charged ion)
- Anion (negatively charged ion)
1.
Normal consciousness?
A balance between excitatory and inhibitory influences.
Name the two types of neurotransmitters that are important for the brain?
Glutamate and GABA
Glutamate
Interact with the binding site with a lock and key effect
Allows sodium to travel down its gradient.
GABA?
Interacts with their binding site with a lock and key effect.
Allows chloride to travel down.
Neuronal excitability
The summation of multiple excitatory inputs initiates an AP.
Inhibitory synpases can prevent the excitatory event.
aS13
What happens during seizures?
EEG: high amplitude during seizure.
Much larger in amplitude and must more less sychronised.
Post midazolam: stimulates GABA system- stop a seizure
Sedations used to control seizures?
Midazolam: induces a state similar to sleep.
Propofol: flat line the EEG. Abolises all brain function. Genereal anestertic.
General anaesteritics are powerful and can enhance GABA effects and synthesis.
GABAA receptor?
Allosteric binding site: GABA.
Steroids: endogenous.
Inverse antagonist is bicuculine and gabazine.
Propofol?
Binds to the barbiturate site of the GABAA receptor.
Patch clamp recording?
AS14
Technique used to determine the function of channels (those within the patch clamp).
Inside out: good as you change the electrical activity.
Outside out: best to look at neurotransmitter activity. Can record the electrical activity.
What receptors does propofol modulates?
GABAA
Glycine receptors
What does GABAA receptor look like?
5 domains
7TM domains
GABAA receptor activation?
3 state model.
Receptor exist in the unbound state: bound to agonist state and the activation state (only if agonist is potent enough)
Extrasynaptic GABAA receptors?
AS15
GABAA receptors are found a number of different locations.
Extrasynpatic receptors give rise to a tonic current. When there is a lot of electrical activity, spill over of GABA reaches the extrasynaptic receptor.
Tonic current
producing and restoring normal current.
What GABA receptors are responsible for the extrasynpatic tonic current?
alpha4 and alpha 6
How is there so many different types of epilepsy?
As mutations in any of these receptors can affect phasic or tonic current.
BIC?
Non-competitive
Binds from the inside of the cell and plugs the channel.
PIC?
Can cause seizures.
What does BIC do?
It inhibits small tonic current.
Can be reversed by GBZ.
Suggesting BIC binds to the GABA site.
What 3 things can cause epilepsy?
- Affecting the phasic current
- Tonic current spontaneous opening
- Tonic current by GABA agonist
GBZ activity?
Reverses the tonic current.
Structural model on how GABA binds to the receptor
AS16
structural models of pentameric ligand-gated ion channels?
Crystallisation is not able to occur when the loop is present
Homoer receptors?
2 subunit receptor
Ligand gated.
Wont bind GABA properly.
Mutation in alpha1 subunit associated with?
Autosomal dominant juvenile myoclonic epilepsy
ADJME
Mutation in the gamma2 subunit associated with?
Childhood absence epielspy (CAE)
Febrile seizures (FS)
Generalised Epilepsy with febrile seizures (GEFS)
Delta subunit mutation is associated with?
Generalised epilepsy with febrile seizures plus
GEFS
Mutation in the GABA-activated ion channel?
Show sign of seizure
Depends on where the mutation is and what does it affect such as structure or function
Where does the lys residue lie in the GABA receptor?
In the TM2 and tm3
What is neccesary for gating?
The position of the positively charged amino acids.
Need to keep the space fill of the loop- so the b1/b2 loop can fit in it.
What happens if you mutate the alpha subunit?
Change in the type of activity
Short duration of openings
What happens when the gamma subunit mutates?
Reduction in the amount of time the channel stays opened
