The endoplasmic reticulum Ca -ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis.

Activation of microglia is an early immune response to damage in the brain. Although a key role for Ca as trigger of microglial activation has been considered, little is known about the molecular scenario for regulating Ca homeostasis in these cells. Taking into account the importance of the endoplasmic reticulum as a cellular Ca store, the sarco(endo)plasmic reticulum Ca -ATPase (SERCA2b) is an interesting target to modulate intracellular Ca dynamics. We found upregulation of SERCA2b in activated microglia of human brain with Alzheimer's disease and we further studied the participation of SERCA2b in microglial functions by using the BV2 murine microglial cell line and primary microglia isolated from mouse brain. To trigger microglia activation, we used the bacterial lipopolysaccharide (LPS), which is known to induce an increase of cytosolic Ca . Our results showed an upregulated expression of SERCA2b in LPS-induced activated microglia likely associated to an attempt to restore the increased cytosolic Ca concentration. We analyzed SERCA2b contribution in microglial migration by using the specific SERCA inhibitor thapsigargin in scratch assays. Microglial migration was strongly stimulated with thapsigargin, even more than with LPS-induction, but delayed in time. However, phagocytic capacity of microglia was blocked in the presence of the SERCA inhibitor, indicating the importance of a tight control of cytosolic Ca in these processes. All together, these results provide for the first time compelling evidence for SERCA2b as a major player regulating microglial functions, affecting migration and phagocytosis in an opposite manner.