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.

Figure 1

(A) At physiological levels of luminal Ca²⁺, BiP remains bound to PERK, IRE1 and ATF6, suppressing their signalling activity. (B) Ischemia induced depletion of ER luminal calcium. ER protein folding capacity is exceeded causing competitive displacement of BiP from PERK, IRE1 and ATF6. Signalling pathways of the unfolded protein response are triggered when BiP dissociates from PERK, IRE1, and ATF6 allowing their dimerization and activation. In turn, transcription of CHOP and ER chaperones is upregulated. Release of ER Ca²⁺, particularly through IP₃Rs, promotes uptake into mitochondria leading to mitochondrial injury and apoptosis. Store depletion further exacerbates the loss of cytosolic Ca²⁺ homeostasis through STIM-dependent signalling, possibly involving surface expressed Ca²⁺ permeable channels.