NMDA Revision

Question 1

Who characterised the activation profiles of GluN1/GluN2A and GluN1/GluN2B and how?

Answer 1

patch-clamp recordings (Erreger, 2005)

Question 2

What does characterisation of activation profiles GluN1/GluN2A and GluN1/GluN2B suggest?

Answer 2

glutamate binding (k  +1) is rapid, while unbinding (k  −1) is relatively slow

Question 3

What times time for NMDAR to be open and activated?

Answer 3

subsequent conformational changes in the receptor protein, as the GluN1 and GluN2 subunits adjust to the rearrangements resulting from closing of the clam shell-like domains of the agonist binding sites (Furukawa et al., 2005; Mayer, 2006), that take time, before the channel can finally open (state A2R*)

Question 4

How does speed of processing and subunit composition change in the cortex during development (include refs)?

Answer 4

slower (decay time constant −250 ms) early in development (Hestrin, 1992) when GluN2B subunits predominate, and becomes faster (decay time constant ∼80 ms) as GluN2A expression rises (Lu et al., 2001)

Question 5

How were conductances of NMDAR subtypes initially measured?

Answer 5

recording single-channel currents from outside-out patches of Glutamate-stimulated Xenopus oocytes expressing different combinations of recombinant NMDARs consisting of GluN1/GluN2A, GluN1/GluN2B and GluN2/GluN2C.

Question 6

Who found conductances of GluN1/2A and B subtypes?

Answer 6

Colquhoun, 1992

Question 7

Who found conductances of GluNC subtypes?

Answer 7

Stern et al., 1992

Question 8

Who found conductances of GluND subtypes?

Answer 8

Wyllie et al., 1996

Question 9

Who showed differential voltage-dependent Mg block and how?

Answer 9

Currents recorded from Xenopus oocytes expressing wild-type NMDAR channels in the presence of differing concentrations of extracellular Mg2+ and at different voltages showed that channels containing GluN2A and GluN2B subunits were blocked more strongly by Mg2+ than those with GluN2C or GluN2D subunits (Kuner and Schoepfer, 1996)

Question 10

What are the IC50’s of NMDA subtypes?

Answer 10

GluN2A and GluN2B is 2.4 μM and 2.1μM, respectively, whereas it is 14.2 μM for GluN2C, and 10.2 μM for GluN2D (Kuner and Schoepfer, 1996).

Question 11

Who hypothesised that asymmetry of asparagine residues was important for Ca2+ and Mg2+ activity in NMDAR’s?

Answer 11

Wollmuth & Sobolevsky, 2004

Question 12

What drug was thought to be a useful GluN2A blocker initially and why was it shown otherwise?

Answer 12

NVP-AAM077 seemed promising, until it was shown that its KB value was only five times greater for GluN2A than for GluN2B (Frizelle et al., 2006)

Question 13

Who showed that NVP-AAM077 could block NMDAR currents in GluN2A deficient mice?

Answer 13

Berberich et al., 2005

Question 14

What alternative GluN2A antagonists were found and by who?

Answer 14

Bettini et al., 2010

TCN201 and TCN213

Question 15

How do TCN201 and TCN213 block NMDAR’s?

Answer 15

negative, non-competitive allosteric modulators of NMDARs containing GluN2A subunits and act to increase the rate of glycine dissociation from the GluN1 agonist-binding domain

non-competitive block dependent on glycine concentration

Question 16

What do mutations do to TCN201 and TCN213 block and what does this indicate?

Answer 16

mutations of residues present in the interface between GluN1 and GluN2A causes a change in the potency of TCN class of drugs (Hansen et al., 2012) implies that the interface could be a valuable target for new drugs for the modulation of NMDARs.

Question 17

Who found what drug was a selective antagonist for GluN2C/D?

Answer 17

Costa et al., 2009 determined by Schild analysis that compounds such as UBP141, showed a slightly higher selectivity (5-10 times) for the GluN2C/GluN2D containing receptors than for other GluN2 subunits

Question 18

What alternative more selective antagonist has been found for GluN2C/D?

Answer 18

QNZ46, a non-competitive antagonist that has a 50-fold greater selectivity for GluN2C/GluN2D than for other GluN2 subunits

Question 19

What is the issue with QNZ46?

Answer 19

glutamate-binding and thereby activity dependent (Hansen & Traynelis, 2011), which brings with it its own limitations.

Question 20

Who showed that ketamine had subunit dependent selectivity and under what conditions?

Answer 20

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)

Question 21

Who showed that GluN2B was necessary for ketamine’s anti-depressant effects?

Answer 21

Miller et al., 2014