FIGURE 1.

Summary of the Ca²⁺ signaling mechanisms in neurons that regulate cytosolic and mitochondrial Ca²⁺ concentrations. Ca²⁺ enters the cell through voltage gated Ca²⁺ channels (VGCC) following depolarization or through glutamate NMDA receptors. As the cytosolic Ca²⁺ concentration increases, the MCU complex opens and Ca²⁺ enters the mitochondria. Ca²⁺ is rapidly removed from the cytosol via Na⁺/Ca²⁺ exchangers (NCX) and plasma membrane Ca²⁺ ATPases (PMCA). As the cytosolic Ca²⁺ concentration decreases Ca²⁺ is slowly released from the mitochondria through Na⁺/Ca²⁺ (mtNCX) exchangers and H⁺/Ca²⁺ exchangers (mtHCX). Proper Ca²⁺ buffering is critical for normal neuronal functions and neuronal plasticity. Impaired buffering and Ca²⁺ overload leads to the opening of the mPTP and activation of apoptotic pathways and is implicated in many neurological diseases. For simplicity, the ER and other Ca²⁺ organelles are omitted from the model.