Influence of external magnesium ions on the NMDA receptor channel block by different types of organic cations

The NMDA type of ionotropic glutamate receptors plays a unique role in synaptic functions because of high permeability for calcium and because of a voltage-dependent block by endogenous Mg2+. Activity and voltage dependence of the NMDA receptor channel block by organic cations are strongly affected by competition with magnesium ions for the binding site in the channel pore. It complicates prediction of action of NMDA receptor channel blockers in vivo. In the present work we studied the NMDA receptor channel block in the presence of Mg2+ by several organic blockers with different characteristics of voltage dependence and mechanism of action. The action of NMDA receptor channel antagonists was studied in native NMDA receptors of hippocampus CA1 pyramidal neurons isolated from rat brain slices. It was demonstrated that the IC50 values of NMDA receptor channel blockers at −30 mV are increased 1.5–5 times compared with magnesium-free conditions. The voltage dependence of the channel block is decreased, abolished or even inversed in the presence of magnesium. Although simple competition between magnesium ion and organic channel blockers provides a general explanation of the observed effects, certain disagreements were revealed. Diversity in Mg2+ effects on the NMDAR channel block by different organic cations reported herein likely reflects interaction of NMDAR channel blockers with additional binding site(s) and suggests that individual analysis in the presence of Mg2+ is required for newly developed NMDAR channel blocking drugs.

► We studied the NMDA receptor channel block in the presence of Mg2+.
► Organic blockers with different voltage dependence and mechanism of action were used.
► Mg2+ strongly affected activity and voltage dependence in all cases.
► Competition model generally reproduced the data but with some disagreements.
► Individual analysis of Mg2+ influence is required for NMDAR channel blocking drugs.