Plutino S - Sciaccaluga M - Fucile S
NMDA 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 Ca ions through NMDARs, caused by an excessive activation of receptors, leads to excitotoxic neuronal cell death. For this reason, the reduction of Ca 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 showing that extracellular mild acidosis reduces NMDA-evoked whole cell currents, we analyzed the effects of this condition on the NMDARs Ca permeability, measured as "fractional calcium current" (P, i.e. the percentage of the total current carried by Ca ions), of human NMDARs NR1/NR2A and NR1/NR2B transiently transfected in HeLa cells. Extracellular mild acidosis significantly reduces P of both human NR1/NR2A and NR1/NR2B NMDARs, also decreasing single channel conductance in outside out patches for NR1/NR2A receptor. Reduction of Ca flux through NMDARs was also confirmed in cortical neurons in culture. A comparative analysis of both NMDA evoked Ca transients and whole cell currents showed that extracellular H differentially modulate the permeation of Na and Ca through NMDARs. Our data highlight the synergy of two distinct neuroprotective mechanisms during acidosis: Ca entry through NMDARs is lowered due to the modulation of both open probability and Ca permeability. Furthermore, this study provides the proof of concept that it is possible to reduce Ca overload in neurons modulating the NMDAR Ca permeability.