Binding of antagonist, NMDA receptors leads to Inhibition, NMDARs

It is well documented that prolonged/chronic antagonism of NMDARs triggers the downstream KE named inhibition of NMDARs. Shorter term binding to the same receptors may trigger different downstream KEs, such as up-regulation of the NMDARs, resulting in toxic increased influx of calcium and to cell death. Consequently, this information can be captured in other KERs and AOP.

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

To predict how potent an antagonist can be, the half maximal inhibition concentrations (IC50) and the half maximal effective concentration (EC50) of glutamate/glycine induced currents is measured in NMDA receptors from brain slices and cells or in recombinantly expressed receptors. Traynelis et al. 2010 summarised the IC50 values for competitive, noncompetitive and uncompetitive antagonists in different subunits of NMDA receptors. The inhibitory effect (efficacy) of antagonists on NMDA receptors has been found to be dependent on:

-the type of subunits that form the NMDA receptors depending on the developmental stage -the chemical structure of the antagonists

-the binding site of receptor that the antagonists prefer

-how tightly an antagonist binds to the receptor (affinity)

At CA3-CA1 synapses, NMDARs are largely composed of NR1 (NMDA receptor subunit 1)-NR2A or NR1-NR2B containing subunits. Recent, but controversial, evidence has correlated NR1-NR2A receptors with the induction of LTP and NR1-NR2B receptors with LTD. However, LTP can be induced by activation of either subtype of NMDAR and the ratio of NR2A:NR2B receptors has been proposed as an alternative determinant of the direction of synaptic plasticity (Mac Donald et al., 2006).

Pb2+: Although the NR2 subunits have different Zn2+ binding sites i.e. the NR2A-NMDAR binds Zn2+ at a high-affinity site (nM affinity) while the NR2B-NMDAR binds Zn2+ with lower affinity (µM range); the Pb2+ IC50 for wild type NR2A-NMDARs was reported to be 1.3 µM, while the Pb2+ IC50 of wild type NR2B-NMDARs was 1.2 µM (Gavazzo et al., 2008). Similar findings were published by Lasley and Gilbert (1999) using cortical neurons from adult rats. The IC50 for Pb2+ ranged from 1.52 to 4.86 µM, with the ranking of Pb2+ potency in inhibition of NMDA receptor subunits to be NR1b-2A>NR1b-2C>NR1b-2D>NR1b-2AC after experiments that have been conducted in Xenopus oocytes injected with cRNAs for different combinations of NMDA receptor subunits (Omelchenko et al., 1997).

The biophysical properties of rat and human receptors have been mostly assessed through recombinant studies, whereas the pharmacological properties of rat and human NMDA receptors have not been fully explored and compared yet (Hedegaard et al., 2012). Mean channel open times for human NMDA receptor subtypes in recombinant protein studies are similar to those of the corresponding rat NMDA receptor subtypes. However, mean single-channel conductances for human NMDA receptor subtypes appear lower than those of the corresponding rat NMDA receptor subtypes. Regarding pharmacological properties of the receptors, the differences were less than 2-fold and were not observed at the same subtypes for all the antagonists tested, suggesting that the molecular pharmacology of NMDA receptor is conserved between human and rat, although some inter-species differences are seen in IC50 values using two-electrode voltage-clamp recordings (Hedegaard et al., 2012),