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 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.

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

“…The AMPAR-mediated depolarization triggers i) the opening of the voltage-dependent calcium channels (VDCC) and ii) the removal of the Mg 2+ block of Ca 2+ -permeable NMDAR, allowing the influx of Ca 2+ into postsynaptic neurons (Kristian and Siesjo, 1998 influx/efflux and Ca 2+ sequestration (Berridge et al, 2003). Under normal physiological conditions the increase in the postsynaptic [Ca 2+ ]i following activation of glutamatergic synapses triggers signaling events and activates the machinery that prevents a [Ca 2+ ]i overload, such as: i) calcium export via the high affinity and low capacity Ca 2+ -ATPase, and the lower affinity, but with much larger capacity, Na + /Ca 2+ exchanger (Guerini et al, 2005;White and Reynolds, 1995), ii) calcium buffering (Gilabert, 2012;Matthews et al, 2013) and iii) calcium sequestration within intracellular organelles, including mitochondria and the endoplasmic reticulum (ER) (Bodalia et al, 2013;Chinopoulos and Adam-Vizi, 2010). In the ischemic brain, the impairment of homeostatic pathways controlling Ca 2+ influx, efflux and release from intracellular stores induces an accumulation of Ca 2+ inside the cells, overactivating calpains and contributing to cell demise.…”

Triptolide Protects Neurons from Endoplasmic Reticulum Stress-Mediated Apoptosis in Cerebral Ischemic Injury Rats

“…The ER is the major site of intracellular Ca 2+ storage, and the segregation of Ca 2+ inside the ER contributes to the maintenance of homeostasis. However, obstructed cerebral blood flow leads to the high levels of toxic products release, which results in the perturbation of homeostasis and Ca 2+ leakage through the ER membrane receptors, leading to the initiation of apoptotic pathway [9,33]. RyRs are the main ER Ca 2+ release channels.…”

Endoplasmic reticulum stress in brain ischemia

“…When the homeostasis is impaired under ischemia, Ca 2+ is released from the ER and causes neuronal insult. The reduction of ER Ca 2+ storage mainly occurs through the activation of ryanodine receptors (RyR) and inositol 1,4,5,-triphosphate receptors (IP 3 R), as well as through the inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPase pump (SERCA) [40].…”

“…High levels of intracellular Ca 2+ evoke RyR activation, leading to the depletion of Ca 2+ in the ER and a further increase of cytosolic Ca 2+ , a process termed Ca 2+ -induced Ca 2+ release (CICR) [42]. Under the influence of ischemia, energy stores are drained, neurons suffer depolarization, and ionic balance no longer exists, resulting in the activation of glutamate receptor (GluR) and Ca 2+ channels as well as the accompanying excitotoxic glutamate release [40]. Receptormediated cytoplasmic Ca 2+ overload further promotes the generation of the toxic products, ROS and NO.…”