4. AMPA receptors: structure, function and trafficking Flashcards
Describe the chain of events leading from glutamate binding to AMPA receptor channel opening and eventual closure
- ligand binding: glu binds between 2 lobes of LBD segments S1 & S2 -> closure amount of LBD correlating to agonist efficacy
- activity cycle: LBD closure -> transmembrane segments are pulled apart -> channel opening -> unstable state of open channel
- decay of currents either by deactivation or desensitation.
What is desensitization of AMPA receptors and how does it differ from deactivation
deactivation = reversal of activation due to ligand unbinding
or
desensitization = decay of current because of spontaneous conformational shift in receptor to a stable state (a bit slower), while ligand is still bound. Rate of desensitization is influenced by accessory proteins and subunit composition & can be prevented by cyclothiazide and point mutations.
What is RNA editing, how does it effect AMPA-R properties
Q -> R editing: ADAR2 converts a specific adenosine in GluA2 into inosine -> positively charged R unit inhibits Ca 2+ permeability: necessary to prevent excitotoxicity
AND repelling of the voltage-dependent block by intracellular polyamines -> allowing channel properties
How can posttranslational modifications regulate AMPA-R properties
phosphorylation, ubiquitination, palmitoylation and accessory proteins regulate trafficking and AMPA-R properties: synaptic AMPA-R density, synaptic plasticity, AMPA-R kinetics
TARPS; CNIHs; CKAMPs; GSG1L
most studied = stargazing (member of TARP family) -> causes: increase in glutamate affinity, decrease in sensitivity kinetics, decrease in deactivation kinetics, polyamine affinity increase
how are changes in synaptic strength caused:
by changes in AMPA-R function -> by changes in number, subunit composition and biophysical properties of AMPA receptors
what are the most common AMPA-R subunit compositions
GluA1/A2 -> major subtype in hippocampal pyramidal cells (CA1)
GluA2/A3
GluA2/A4
GluA1
GluA4
