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

Abstract

The loss of Ca(2+) homeostasis during cerebral ischemia is a hallmark of impending neuronal demise. Accordingly, considerable cellular resources are expended in maintaining low resting cytosolic levels of Ca(2+). These include contributions by a host of proteins involved in the sequestration and transport of Ca(2+), many of which are expressed within intracellular organelles, including lysosomes, mitochondria as well as the endoplasmic reticulum (ER). Ca(2+) sequestration by the ER contributes to cytosolic Ca(2+) dynamics and homeostasis. Furthermore, within the ER Ca(2+) plays a central role in regulating a host of physiological processes. Conversely, impaired ER Ca(2+) 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 Ca(2+) elevations during ischemia will be considered, as will the signalling cascades recruited as a consequence of disrupting ER homeostasis and function.