Extracellular mild acidosis reduces the Ca2+ permeability of NMDA receptors

N-methyl-D-Aspartate receptors (NMDARs) are glutamate gated ion channels involved in excitatory synaptic transmission and in others physiological processes such as synaptic plasticity and development. The overload of Ca2+ ions through NMDARs, caused by an excessive activation of receptors, leads to excitotoxic neuronal cell death, which occurs in several neurological disorders. For this reason, the reduction of Ca2+ flux through NMDARs has been a central focus in finding therapeutic strategies to prevent neuronal cell damage. Extracellular H+ are allosteric modulators of NMDARs. Starting from previous studies which demonstrated that extracellular mild acidosis reduces NMDA evoked whole cell current, we studied the effect of extracellular mild acidosis on the NMDARs Ca2+ permeability measured as “fractional calcium current” (Pf, i.e. the percentage of the total current carried by Ca2+ ions) for human NMDARs NR1/NR2A and NR1/NR2B transiently transfected in HeLa cells. Here, we report that extracellular mild acidosis significantly reduces Pf of both human NR1/NR2A and NR1/NR2B NMDARs, decreasing also the single channel conductance in outside out patches for NR1/NR2A receptor. Reduction of Ca2+ flux through NMDARs is also confirmed in cortical neurons in culture. Furthermore, analysis of both NMDA evoked Ca2+ transients and whole cell currents in extracellular mild acidosis showed that extracellular H+ differentially modulate the ionic permeation (Na+ and Ca2+) through NMDARs. Here we show that extracellular H+ limit Ca2+ entry through NMDA receptors, highlighting a protective mechanism by which the NMDARs Ca2+ flux is regulated during acidic shifts of extracellular pH.