Inhibition, NMDARs leads to Decreased, Calcium influx

The structural diversity of NMDA subunits can influence the functionality of the receptors and their permeability to Ca2+. For example, NR2B subunits show higher affinity for glutamate binding and higher Ca2+ permeability (reviewed in Higley and Sabatini, 2012). But NMDA receptor subunit composition is not the only parameter that influences Ca2+ entrance in the cytosol. Membrane potential due to pore blockade by extracellular Mg2+ and receptor phosphorylation are two additional regulator of Ca2+ influx through NMDA receptors (reviewed in Higley and Sabatini, 2012).

Entrance of Ca2+ into neuronal cell can also happen through KA and AMPA receptors but to a smaller extent compared to NMDA receptors (reviewed in Higley and Sabatini, 2012). However, recent findings suggest that AMPA receptors may also contribute to Ca2+ signalling during CNS development (reviewed in Cohen and Greenberg, 2008). Early in development cortical pyramidal neurons express calcium-permeable, GluR2 subunit–lacking AMPA receptors. During postnatal development these neurons undergo a switch in the subunit composition of AMPA receptors, expressing instead GluR2-containing, calcium-impermeable AMPA receptor suggesting that the main point entrance of Ca2+ at this developmental stage are NMDA receptors.

Furthermore, Ca2+ entry occurs through L- and H-type voltage-dependent Ca2+channels (L-VDCCs) (Perez-Reyes and Schneider, 1994; Berridge, 1998; Felix, 2005) that are encountered in neurons, suggesting that there are more possible entrance sites for Ca2+ to get into the cytosol rather than only through NMDA receptors.

Interestingly, Pb2+ has the ability to mimic or even compete with Ca2+ in the CNS (Flora et al., 2006). Indeed, Pb2+ is accumulated in the same mitochondrial compartment as Ca2+ and it has been linked to disruptions in intracellular calcium metabolism (Bressler and Goldstein, 1991). So, it can be that the reduced levels of Ca2+ after Pb2+ exposure may not be attributed to NMDA receptor inhibition but also to the ability of this heavy metal to compete with Ca2+. To make things more complicated, recent findings suggest that BDNF can also acutely elicit an increase in intracellular Ca2+ concentration, which is attributed not only to the influx of extracellular Ca2+ but also to Ca2+ mobilization from intracellular calcium stores (Numakawa et al., 2002; He et al., 2005). These findings derive from primary cultures of cortical neurons (E18 or 2-3 PND), where BDNF-evoked Ca2+ signals have not been altered neither by tetrodotoxin nor by a cocktail of glutamate receptor blockers (CNQX and APV), pointing out the importance of BDNF in Ca2+ homeostasis (Numakawa et al., 2002; He et al., 2005).