Regulator of G protein Signaling 10 (RGS10) functionally interacts with store-operated calcium entry machinery to regulate COX-2 and TNF-alpha in Microglia

Activation of microglia is a driving factor of neuroinflammation and a hallmark of neurodegenerative diseases. The central inflammatory enzyme cyclooxygenase 2 (COX‐2) and the pro‐inflammatory cytokine tumor necrosis factor‐alpha (TNF‐α) mediate critical features of microglial activation responses, and their upregulation in the brain is a characteristic feature of many neurodegenerative diseases and brain injury. The Regulator of G protein Signaling 10 (RGS10), a small RGS protein enriched in microglia, has G protein‐independent functions in suppressing lipopolysaccharide (LPS)‐induced expression of COX‐2 and TNF‐α. Herein, we identify a biochemical and functional interaction between RGS10 and the endoplasmic reticulum (ER)‐localized calcium sensor STIM2, which is an essential component of the store‐operated calcium entry (SOCE) machinery. We determined that STIM2 and its downstream calcium pathway, particularly Orai channels and the Ca 2+ ‐dependent phosphatase calcineurin, are essential for LPS‐induced COX‐2 and TNF‐α production in microglia, and likewise this pathway mediates the inhibitory effect of RGS10 on LPS‐signaling. We further demonstrated that ER calcium depletion amplifies LPS‐induced COX‐2 and TNF‐α expression and that RGS10 functions to suppress SOCE triggered by ER depletion. Collectively, this physical and functional interaction between RGS10 and STIM2 in microglia suggest a complex regulatory network connecting RGS10, LPS‐signaling, and SOCE, with broad implications in the pathogenesis and treatment of chronic neuroinflammation. Support or Funding Information NIH‐NINDS