Astrocyte glycogenolysis is triggered by store‐operated calcium entry and provides metabolic energy for cellular calcium homeostasis. Issue 4 (24th January 2014) - Müller, Margit S.
Abstract Astrocytic glycogen, the only storage form of glucose in the brain, has been shown to play a fundamental role in supporting learning and memory, an effect achieved by providing metabolic support for neurons. We have examined the interplay between glycogenolysis and the bioenergetics of astrocytic Ca2+ homeostasis, by analyzing interdependency of glycogen and store‐operated Ca2+ entry (SOCE), a mechanism in cellular signaling that maintains high endoplasmatic reticulum (ER) Ca2+ concentration and thus provides the basis for store‐dependent Ca2+ signaling. We stimulated SOCE in primary cultures of murine cerebellar and cortical astrocytes, and determined glycogen content to investigate the effects of SOCE on glycogen metabolism. By blocking glycogenolysis, we tested energetic dependency of SOCE‐related Ca2+ dynamics on glycogenolytic ATP. Our results show that SOCE triggers astrocytic glycogenolysis. Upon inhibition of adenylate cyclase with 2', 5'‐dideoxyadenosine, glycogen content was no longer significantly different from that in unstimulated control cells, indicating that SOCE triggers astrocytic glycogenolysis in a cAMP‐dependent manner. When glycogenolysis was inhibited in cortical astrocytes by 1, 4‐dideoxy‐1, 4‐imino‐D‐arabinitol, the amount of Ca2+ loaded into ER via sarco/endoplasmic reticulum Ca2‐ATPase (SERCA) was reduced, which suggests that SERCA pumps preferentially metabolize glycogenolytic ATP. Our study demonstrates SOCE as a novel pathway in stimulating astrocytic glycogenolysis. We also provide first evidence for a new functional role of brain glycogen, in providing local ATP to SERCA, thus establishing the bioenergetic basis for astrocytic Ca2+ signaling. This mechanism could offer a novel explanation for the impact of glycogen on learning and memory. GLIA 2014;62:526–534