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. (C) 2009 Elsevier Ltd. All rights reserved.