The trinity of Ca2+ sources for the exocytotic glutamate release from astrocytes

Astrocytes can exocytotically release the transmitter glutamate. Increased cytosolic Ca2+ concentration is necessary and sufficient in this process. The source of Ca2+ for the Ca2+-dependent exocytotic release of glutamate from astrocytes predominately comes from endoplasmic reticulum (ER) stores with contributions from both inositol 1,4,5-trisphosphate- and ryanodine/caffeine-sensitive stores. An additional source of Ca2+ comes from the extracellular space via store-operated Ca2+ entry due to the depletion of ER stores. Here transient receptor potential canonical type 1 containing channels permit entry of Ca2+ to the cytosol, which can then be transported by the store-specific Ca2+-ATPase to (re)fill ER. Mitochondria can modulate cytosolic Ca2+ levels by affecting two aspects of the cytosolic Ca2+ kinetics in astrocytes. They play a role in immediate sequestration of Ca2+ during the cytosolic Ca2+ increase in stimulated astrocytes as a result of Ca2+ entry into the cytosol from ER stores and/or extracellular space. As cytosolic Ca2+declines due to activity of pumps, such as the smooth ER Ca2+-ATPase, free Ca2+ is slowly released by mitochondria into cytosol. Taken together, the trinity of Ca2+ sources, ER, extracellular space and mitochondria, can vary concentration of cytosolic Ca2+ which in turn can modulate Ca2+-dependent vesicular glutamate release from astrocytes. An understanding of how these Ca2+ sources contribute to glutamate release in (patho)physiology of astrocytes will provide information on astrocytic functions in health and disease and may also open opportunities for medical intervention.