NMDAR revision 2 Flashcards
What is the EC50 of glutamate binding to GluN2?
2uM
What does the addition of exon5 do to GluN2B containing receptors (and who showed this?
Increase deactivation rate by 3-4 fold
Rumbaugh, 2000
How do heterotrimeric GluN1/2A/2B receptors differ in response to ifenprodil and who showed this?
Reduced maximal effect as evidenced by slower onset of drug action and faster offset
Tovar and Westenbroek 1999
What does the CTD consist of?
Tyrosine kinase phosphorylation and binding sites
What does the M2 form?
A re-entrant loop from the inside which lines the major part of the channel pore and regulates Ca2+ and Mg2+ with crucial arginine residues (Wollmouth, 1998)
Where is the proton sensitivity site?
In the NTD
What is the importance of proton sensitivity?
Under physiological conditions, blocks 50% NMDAR’s - Traynelis and Cull-Candy, 1990
What is the most obvious different in transmembrane topology between subtypes?
Length of CTD
GluN2A/B = longest
GluN1/3B = shortest
What position was the S residue changed to L to show subtype specific Mg2+ block in GluN2A?
S632 in M3
Why might GluN3 be insensitive to Mg2+?
No Arginine in M2
What is a way of measuring Ca2+ permeability?
Single channel conductance
What does Mg2+ block do to the synaptic current?
selective block at negative potentials
As the membrane becomes depolarised, the Mg2+ is expelled from the pore allowing charge to flow into the cell, meaning that synaptic currents are prolonged when the membrane is depolarised.
NMDAR decays with a double-exponential decay - what is the time course of the first decay and who found this?
200 ms , Spruston 1995
Why might unbinding of agnonist and desensitization affect the decay time course of EPSC?
- prolonged activation after short period of agonist application - Lester 1990
- Desensitization in continued presence of agonsit
What type of study was used to show that GluN2 containing subunits have different decay time course?
In an outside-out patch, in the presence of a brief pulse of agonist, the NMDAR-mediated current displays a characteristic decay time course that depends on the identity of the GluN2 subunit
What is the time course decay ratio between GluN1-1b and GluN1-1a receptors?
tW = 1:4
What is a use-dependent GluNC/D blocker?
QNZ46
a non-competitive antagonist that has a 50-fold greater selectivity for GluN2C/GluN2D than for other GluN2 subunits
but glutamate binding - use dependent
Hansen & Traynelis, 2011
What is a non-competitive GluN2C/2D antagonist?
DQP-1105 inhibited GluN2C- and GluN2D-containing receptors with IC50 values that were at least 50-fold lower than those for other GluN2 recombinant receptors. Inhibition was voltage-independent and could not be surmounted by increasing concentrations of either coagonist, glutamate or glycine, consistent with a noncompetitive mechanism of action (Acker et al.,2011)
Is ketamine subunit selective? under what conditions?
when acting on receptors expressing GluN1/GluN2C subunits, has a three to four times greater potency than when acting on NMDARs containing other GluN2 subunits, but only in the presence of extracellular Mg2+ (Khlestova et al., 2016)
How do we know that GluN2B mediates the anti-depressant effect of ketamine>
deletion of GluN2B in vivo from principal cortical neurons imitating the anti-depressant action of Ketamine (Miller et al., 2014)
What does ketamine and memantine block depend on?
Both open channel block by Ketamine and Memantine depends on the asparagine residue in M2 in GluN1/GluN2 subunits. Thus, NMDAR’s containing GluN3 subunits are less effectively blocked
What is a GluN2A specific antagonist and how does it work?
TCN201 and TCN213 which produce a non-competitive block dependent on glycine concentration by increasing the rate of glycine dissociation from the GluN1 agonist-binding domain in GluN2A containing NMDAR’s (Bettini et al., 2010)
