Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes

Abstract

Overactivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca2+ overload and excitotoxic death, a process that contributes to demyelination and multiple sclerosis. Excitotoxic insults cause well-characterized mitochondrial alterations and endoplasmic reticulum (ER) dysfunction, which is not fully understood. In this study, we analyzed the contribution of ER-Ca2+ release through ryanodine receptors (RyRs) and inositol triphosphate receptors (IP3Rs) to excitotoxicity in oligodendrocytes in vitro. First, we observed that oligodendrocytes express all previously characterized RyRs and IP3Rs. Blockade of Ca2+-induced Ca2+ release by TMB-8 following α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor-mediated insults attenuated both oligodendrocyte death and cytosolic Ca2+ overload. In turn, RyR inhibition by ryanodine reduced as well the Ca2+ overload whereas IP3R inhibition was ineffective. Furthermore, AMPA-triggered mitochondrial membrane depolarization, oxidative stress and activation of caspase-3, which in all instances was diminished by RyR inhibition. In addition, we observed that AMPA induced an ER stress response as revealed by α subunit of the eukaryotic initiation factor 2α phosphorylation, overexpression of GRP chaperones and RyR-dependent cleavage of caspase-12. Finally, attenuating ER stress with salubrinal protected oligodendrocytes from AMPA excitotoxicity. Together, these results show that Ca2+ release through RyRs contributes to cytosolic Ca2+ overload, mitochondrial dysfunction, ER stress and cell death following AMPA receptor-mediated excitotoxicity in oligodendrocytes.

Ca2+‐dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β‐treated astrocytes and in a model of Alzheimer's disease

“…In the present study, we demonstrated that amyloid b oligomers induced ER stress in astrocytes in vitro and in vivo. We observed robust phosphorylation of eIF2a, together with an increased expression of the GRP78 ERresident chaperones, which are hallmarks of neuronal and glia injury-related UPR (Ruiz et al, 2009(Ruiz et al, , 2010. We additionally showed that ER Ca 2+ release through RyRs and InsP 3 Rs was involved in this response; inhibition of both types of receptors diminished eIF2a phosphorylation and the GRP78 increase, most likely by preventing ER Ca 2+ depletion.…”

Protecting White Matter From Stroke Injury

“…14 Oligodendrocytes, not axons, are the primary victims of WM excitotoxicity. Overactivation of oligodendrocyte glutamate receptors causes Ca 2+ overload of the cytosol leading to endoplasmic reticulum stress, 76 mitochondrial depolarization, oxidative stress, Bax-mediated, caspase-dependent and -independent cell death, and myelin destruction. 12,77 Thus, oligodendrocytes can be partially protected from irreversible ischemic injury, including perinatal ischemia, by glutamate receptor antagonists and glutamate uptake inhibitors 11,[16][17][18][19][20] (Table; Figure 3; refs.…”

Ca2+ store depletion and endoplasmic reticulum stress are involved in P2X7 receptor‐mediated neurotoxicity in differentiated NG108‐15 cells

“…It has been reported that stimulation of the receptors for aamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA receptor, an ionotropic glutamate receptor subtype) causes ER stress, Ca 2þ overload, and cytotoxicity in oligodendrocytes [Ruiz et al, 2010]. In this work, pharmacological inhibition of RYR, but not of IP3R, could reduce Ca 2þ overload and cell death, suggesting the involvement of RYR-mediated Ca 2þ release in AMPA receptortriggered excitotoxicity.…”