Figure 2

Neuronal Ca²⁺signaling. Cytosolic [Ca²⁺]_i rises are the result of an influx across the plasma membrane via voltage-gated Ca²⁺channels (VGCCs), ionotropic glutamate receptors (N-Methyl-D-Aspartic acid receptors, NMDARs; and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate, AMPARs), and the release from the ER through the inositol 1,4,5-trisphosphate (IP₃R) and the ryanodine (RyR) receptors. Intraneuronal Ca²⁺ compartmentalization, is also maintained by the activity of Ca²⁺-binding buffering proteins (e.g., calbindin and parvalbumin), and regulated within signaling microdomains which involve, ATP-dependent Ca²⁺ pumps SERCA (Sarco-Endoplasmic Reticulum Ca²⁺ ATPase) accumulating Ca²⁺ from the cytosol to ER, and the sodium-Ca²⁺ exchanger (Na⁺/Ca²⁺), which act together with PMCA (Plasma Membrane Ca²⁺ ATPase) to restore [Ca²⁺]_i back to resting levels by extruding Ca²⁺ from the cytosol to the extracellular space. Although much of the Ca²⁺ entry into neuron is predominantly mediated by plasma membrane channels, IP₃R- and/or RyR-mediated Ca²⁺ release can be subsequently recruited via the phenomenon of Ca²⁺-induced Ca²⁺ release (CICR), a regenerative process in which Ca²⁺ enhances its own release from IP₃R and RyR.