Coupling of the NMDA receptor to neuroprotective and neurodestructive events

Abstract

NMDA (N-methyl-D-aspartate) receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca(2+) influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischaemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington's disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render neurons vulnerable to secondary trauma. Thus responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death in response to both hyper- and hypo-activity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.

Fig. 1. Neuroprotective signalling by synaptic NMDAR activity

Some examples of anti-apoptotic and antioxidant signalling events that can promote neuroprotection. See text for details.

Fig. 2. Synaptic NMDAR activity boosts intrinsic antioxidant defences

A schematic showing impact of activity-dependent changes in gene expression on the thioredoxin-peroxiredoxin cycle (events shaded in grey). Briefly, detoxification of peroxides is mediated through the transfer of reducing equivalents from NADPH to peroxides via the redox-active sulfhydryl (-SH) groups of thioredoxin and peroxiredoxins (Prx, the two-cysteine peroxiredoxin major subtype is shown here). The redox active −SH group of Prx is oxidized to −SOH by peroxides. Ordinarily this converts to a disulfide bond upon reaction with the resolving cysteine −SH group, which is in turn reduced by thioredoxin, returning Prx back to its reduced form. If levels of peroxide get to high or thioredoxin/peroxiredoxin activity too low, the −SOH group becomes hyperoxidized to −SO₂H (cysteine sulfinic acid) which is not a substrate for the resolving cysteine or for thioredoxin. Instead, sulfiredoxin (and possibly sestrin 2) catalyses the reduction of hyperoxidized Prx-SO₂H and returns is to the thioredoxin cycle. Synaptic activity triggers the events shown (and described in the text) to both enhance thioredoxin activity and boost the reduction of hyperoxidized Prxs.

Fig. 3. Neurodestructive signalling by NMDAR activity

Some examples of excitotoxic signalling events promoted by NMDAR activity. Note that some of these events, such as CREB inactivation, calpain-mediated STEP cleavage and disruption of mitochondrial membrane potential are preferentially triggered by chronic extrasynaptic NMDAR activation, rather than trans-synaptic activation of synaptic NMDARs. See text for details.