Figure 1. Sources of Ca²⁺ in Ca²⁺-dependent glutamate release from astrocytes.

The accumulation of Ca²⁺ in cytosol could be caused by the entry of Ca²⁺ from the ECS through: (i) L-type VGCC [blocked by nifedipine (Nif)]; (ii) SOCE via TRPC1 containing channels [blocked by antibodies against the channel pore (Ab)]; and (iii) the plasma membrane NCX (the reverse mode blocked by KB-R7943). The predominant source of Ca²⁺ is available from the ER internal store that possess InsP₃R (blocked by 2-APB, which can also block SOCE) and RyR [blocked by ryanodine (Ry)] channels acting as conduits for Ca²⁺ delivery to the cytosol. The ER store is (re)filled by SERCA [blocked by thapsigargin (Thaps)]. Cytosolic Ca²⁺ levels are modulated by mitochondria that can take-up Ca²⁺ via the Ca²⁺ uniporter (blocked by Ru360) during the cytosolic Ca²⁺ increase. As cytosolic Ca²⁺ declines due to extruding mechanisms, Ca²⁺ is slowly released by mitochondria into cytosol via the mitochondrial NCX (blocked by CGP37157) as well as by the formation of the mitochondrial permeability transition pore [its opening blocked by cyclosporin A (CsA)]. The increase in cytosolic Ca²⁺ levels is sufficient and necessary to cause the fusion of glutamatergic vesicles to the plasma membrane and exocytotic release of glutamate. Drawing is not to scale.