Loss of endoplasmic reticulum Ca2+ homeostasis: contribution to neuronal cell death during cerebral ischemia

The loss of Ca²⁺ homeostasis during cerebral ischemia is a hallmark of impending neuronal demise. Accordingly, considerable cellular resources are expended in maintaining low resting cytosolic levels of Ca²⁺. These include contributions by a host of proteins involved in the sequestration and transport of Ca²⁺, many of which are expressed within intracellular organelles, including lysosomes, mitochondria as well as the endoplasmic reticulum (ER). Ca²⁺ sequestration by the ER contributes to cytosolic Ca²⁺ dynamics and homeostasis. Furthermore, within the ER Ca²⁺ plays a central role in regulating a host of physiological processes. Conversely, impaired ER Ca²⁺ homeostasis is an important trigger of pathological processes. Here we review a growing body of evidence suggesting that ER dysfunction is an important factor contributing to neuronal injury and loss post-ischemia. Specifically, the contribution of the ER to cytosolic Ca²⁺ elevations during ischemia will be considered, as will the signalling cascades recruited as a consequence of disrupting ER homeostasis and function.