Astroglial Ca²⁺ signaling is generated by the coordination of IP₃R and store-operated Ca²⁺ channels

Astrocytes play key roles in the central nervous system and regulate local blood flow and synaptic transmission via intracellular calcium (Ca²⁺) signaling. Astrocytic Ca²⁺ signals are generated by multiple pathways: Ca²⁺ release from the endoplasmic reticulum (ER) via the inositol 1, 4, 5-trisphosphate receptor (IP₃R) and Ca²⁺ influx through various Ca²⁺ channels on the plasma membrane. However, the Ca²⁺ channels involved in astrocytic Ca²⁺ homeostasis or signaling have not been fully characterized. Here, we demonstrate that spontaneous astrocytic Ca²⁺ transients in cultured hippocampal astrocytes were induced by cooperation between the Ca²⁺ release from the ER and the Ca²⁺ influx through store-operated calcium channels (SOCCs) on the plasma membrane. Ca²⁺ imaging with plasma membrane targeted GCaMP6f revealed that spontaneous astroglial Ca²⁺ transients were impaired by pharmacological blockade of not only Ca²⁺ release through IP₃Rs, but also Ca²⁺ influx through SOCCs. Loss of SOCC activity resulted in the depletion of ER Ca²⁺, suggesting that SOCCs are activated without store depletion in hippocampal astrocytes. Our findings indicate that sustained SOCC activity, together with that of the sarco-endoplasmic reticulum Ca²⁺-ATPase, contribute to the maintenance of astrocytic Ca²⁺ store levels, ultimately enabling astrocytic Ca²⁺ signaling.