David Flashcards
(AMPARs, NMDARs, diseases)
What diseases are associated with nAChR dysfunction?
Epilepsy: mutation in M2 loop in a4 subunit- gating mutation (reduced permeability)
Severe myasthenia syndrome: mutation in cys loop increases unbinding of ACh
M2 is pore lining region
What diseases are associated with NMDAR dysfunction?
Intellectual disability and epilepsy: GluN2A M2 region (N615K), blocks Mg+ block and reduces permeability
Epilepsy aphasia syndrome: GluN2A pre-M1 region (T531M, R518H), gating mutation= increased opening and slower NMDA decay; NTD (A243V) reduces Zn+ inhibition
Early-onset epileptic encephalopathy: GluN2A pre-M4 region (L812M), inc potency for glutamate and glycine and decreased decay
Asp (N) is negative and Lys (K) is positive
Zinc inhibits NDMAR with 2A subunit
What diseases are associated with AMPAR?
ALS: theres more Ca2+ permeable AMPARs (non-GluA2) which causes greater susceptibility to glutamate-toxicity induced motor neuron death
What is the evidence that hyperekplexia is a gating mutation?
- Its a K276E mutation in the M2-3 region on a glycine recpetor (pos charge on glutamate will repel the Cl- from entering the pore since its in M2-3)
- Binding is unaffected since strychnine binds fine (has same binding site as glycine)
- From single channel recordings, there is lower conductance and lower opening time (both indicative of a gating mutation)
- Decrease in Hill slope (big indicator of a gating mutation)
- The dose response curve is shifted to the right (aka reduced potency) and the peak amplitude is decreased (mainly affects effiacy of channel after determining the E)
What are the differences between the different NMDA subunits?
GluN21 (essential, binds glycine
GluN2A (only expressed in adult, highest conductance, most sensitive to Mg2+ block, neuroprotective)
GluN2B (expressed in early development, more likely to mediate glutamate toxicity)
GluN2C (expressed in adult in cerebellum granule cells)
GluN2D (only in early development in interneurons in hippocampus, very slow, highest potency for glutamate, slowest deactivation, slowest conductance)
2A conductance is higher bc in 2A and B there is a serine residue at 632 but in C and D there is a leucine at the homolgous position at 657, if you flip these around then C D are fast and A B are slow-> these residues determine conductance
How does AMPAR mediate synaptic plasticity?
After AMPAR phoshporylation there is increased conductance and trafficking (LTP), removal of AMPAR results in LTD
How is memantine used to treat early-onset epileptic encephalopathy?
It is a use-dependant blocker: in high periods of activity (caused by the GluN2A mutation) it blocks NMDARs pore. Very effective when used in combo with valproate
Why are NMDAs referred to as coincidence detectors?
Because unlike AMPARs which are just ligand gated, NMDAs are also voltage-dependent, the membrane needs to be depolarised enough to remove the Mg2+ ion from the pore as well as having glutamate or an agonist bound to the receptor
