Inositol 1,4,5‐trisphosphate receptor type 2‐independent Ca2+ release from the endoplasmic reticulum in astrocytes

Abstract Accumulating evidence indicates that astrocytes are actively involved in the physiological and pathophysiological functions of the brain. Intracellular Ca 2+ signaling, especially Ca 2+ release from the endoplasmic reticulum (ER), is considered to be crucial for the regulation of astrocytic functions. Mice with genetic deletion of inositol 1,4,5‐trisphosphate receptor type 2 (IP 3 R2) are reportedly devoid of astrocytic Ca 2+ signaling, and thus widely used to explore the roles of Ca 2+ signaling in astrocytic functions. While functional deficits in IP 3 R2‐knockout (KO) mice have been found in some reports, no functional deficit was observed in others. Thus, there remains a controversy regarding the functional significance of astrocytic Ca 2+ signaling. To address this controversy, we re‐evaluated the assumption that Ca 2+ release from the ER is abolished in IP 3 R2‐KO astrocytes using a highly sensitive imaging technique. We expressed the ER luminal Ca 2+ indicator G‐CEPIA1 er in cortical and hippocampal astrocytes to directly visualize spontaneous and stimulus‐induced Ca 2+ release from the ER. We found attenuated but significant Ca 2+ release in response to application of norepinephrine to IP 3 R2‐KO astrocytes. This IP 3 R2‐independent Ca 2+ release induced only minimal cytosolic Ca 2+ transients but induced robust Ca 2+ increases in mitochondria that are frequently in close contact with the ER. These results indicate that ER Ca 2+ release is retained and is sufficient to increase the Ca 2+ concentration in close proximity to the ER in IP 3 R2‐KO astrocytes.