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A tingle of extra excitement with voltage dependence of NMDA receptor activation

The NMDA receptor is something of a grand old lady of neuroscience. Her slow kinetics convey an appropriate stateliness for a channel used to being waited on by other racier conductances. Long the subject of intense scrutiny, only occasionally now do we glimpse a hitherto overlooked characteristic that highlights a new fascinating wrinkle. In this issue of The Journal of Physiology, Clarke & Johnson (2008) uncover the surprising result that NMDA receptors have, after all, a voltage-sensitive component to their gating. The generally accepted view has been that NMDA receptors show no inherent voltage sensitivity, all their prodigious voltage dependence being endowed by Mg2+ block. 
 
Slow activation and deactivation, combined with a steeply voltage-dependent Mg2+ block (Ascher & Nowak, 1988) means that NMDA receptors can function as ‘coincidence detectors’, a property central to the idea that, ‘neurons that fire together, wire together’. Current, and particularly calcium influx, through the channel is boosted whenever a depolarization, such as a synaptic potential or back-propagating action potential, occurs during the time when the receptors are activated (Spruston, 2008). For effective coincidence detection, timing is critical, making the NMDA receptor kinetics of particular interest in understanding this role. 
 
Given the dominance of the voltage dependence endowed by Mg2+ block, why is an extra, inherent voltage dependence of the NMDA receptor gating significant?Clarke & Johnson (2008) show that after an action potential, this voltage dependence will result in up to 50% extra current through the channel because while the membrane potential is at positive voltages the channel open probability increases, and this then takes a few milliseconds to ‘relax’ back to the steady-state after the action potential. A slow component of Mg2+ unblock has been described by several labs and was elegantly modelled by Vargas-Caballero & Robinson (2004) using an asymmetric trapping block model. Crucially, Clarke & Johnson show that the slow relaxation is evident even in the absence of Mg2+ and so is not dependent on Mg2+ block but is an inherent property of the NMDA receptor. Interestingly, Clarke & Johnson (2006) have previously shown that the slow component observed with 2A and 2B receptors is not seen with 2C or 2D receptors and in this paper 2D receptors are shown to lack voltage dependence in the absence of Mg2+ (Supplemental Fig. 3). Thus the calcium boost delivered by active 2A or 2B receptors will be absent for 2D receptors. This leaves open the question of what will be the behaviour of a triheteromeric NR1/2B/2D receptor (Brothwell et al. 2008). The clue that 2A or 2B receptors, but not 2D receptors display voltage dependence suggests that voltage dependence is conferred by the NR2 subunit. Clarke & Johnson therefore model their results based on the Banke & Traynelis (2003) model of NMDA receptor gating that associates kinetically distinct pregating conformational changes with the NR1 and NR2 subunits. They show that a model where only the rate of the slow forward conformational change of the NR2 subunit (k+s) is made voltage dependent is sufficient to describe the data. Using this model Clarke & Johnson show that Mg2+ block can then be modelled without asymmetry of the rates between Mg2+-bound and Mg2+-free ‘arms’ of the model. The absence of any need for asymmetry of the blocking model concurs with some previous suggestions that when Mg2+ is bound it does not significantly affect the rates of conformational changes in the receptor: the receptor ‘gates’ normally around the Mg2+ ion while it is lodged in the channel. 
 
Why has this escaped detection until now? One reason is that the difficulty of removing all magnesium from physiological salt solutions makes it hard to study NMDA receptors in the complete absence of magnesium, and so any observed voltage dependence in the nominal absence of magnesium is easily ascribed to contamination. Having said that, there have been occasional reports of clear voltage sensitivity of both single channel (Gibb & Colquhoun, 1992; Nowak & Wright, 1992) and macroscopic currents (Benveniste & Mayer, 1995; Spruston et al. 1995). Another reason is that the voltage dependence is most obvious following depolarizing steps to positive voltages, a voltage range not often explored because of the extra technical difficulty of achieving good voltage control at positive voltages. It is significant though, that these are membrane voltages commonly seen at the peak of dendritic action potentials in cortex or hippocampus (Spruston, 2008). 
 
What might be the physical basis of this voltage dependence? The most likely explanation is that it reflects the movement of some charged amino acids located in the receptor structure within the membrane electric field. The voltage sensitivity ascribed to k+s of an e-fold increase for 175 mV depolarization corresponds to a single charge moving through 14% of the membrane electric field. This movement we may suppose somehow affects the rates of the NR2 subunit activation. Who will be the first to mutate an amino acid in the 2A or 2B subunits and make an NMDA receptor that lacks inherent voltage sensitivity? Such a receptor is of more than passing interest because the amino acid in question will be a significant clue to the structural basis of NMDA receptor gating.