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bioRxiv · 10.1101/2023.09.03.556116

Excitotoxic glutamate levels cause the secretion of resident endoplasmic reticulum proteins

Dossat, A. M.·Trychta, K. A.·Fortuno, L. V.·Richie, C. T.·Harvey, B. K.
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Abstract

Dysregulation of synaptic glutamate levels can lead to excitotoxicity such as that observed in stroke, traumatic brain injury, and epilepsy. The role of increased intracellular calcium (Ca2+) in the development of excitotoxicity is well established. However, less is known regarding the impact of glutamate on endoplasmic reticulum (ER)-Ca2+-mediated processes such as proteostasis. To investigate this, we expressed a secreted ER Ca2+ modulated protein (SERCaMP) in primary cortical neurons to monitor exodosis, a phenomenon whereby ER calcium depletion causes the secretion of ER resident proteins that perform essential functions to the ER and the cell. Activation of glutamatergic receptors (GluRs) led to an increase in SERCaMP secretion indicating that normally ER resident proteins are being secreted in a manner consistent with ER Ca2+ depletion. Antagonism of ER Ca2+ channels attenuated the effects of glutamate and GluR agonists on SERCaMP release. We also demonstrate that endogenous proteins containing an ER retention sequence (ERS) are secreted in response to GluR activation supporting that neuronal activation by glutamate promotes ER exodosis. Ectopic expression of KDEL receptors attenuated the secretion of ERS-containing proteins caused by GluR agonists. Taken together, our data indicate that excessive GluR activation causes disruption of neuronal proteostasis by triggering the secretion of ER resident proteins through ER Ca2+ depletion and describes a new facet of excitotoxicity. SignificanceDuring excitotoxicity, the excessive activation of glutamate receptors causes elevated intracellular calcium (Ca2+) that promotes cellular dysfunction and death. While the role of cytosolic Ca2+ in excitotoxicity has been well-studied, the consequences of changes in endoplasmic reticulum (ER) Ca2+ during excitotoxicity remains unclear. The relatively high concentration of calcium in the ER is necessary for ER resident proteins to function prop out essential functions and maintain cellular proteostasis. We show here that excitotoxic conditions destabilize the ER proteome by triggering ER resident protein secretion. Stabilizing ER Ca2+ or overexpressing receptors that interact with ER resident proteins can prevent disruption of proteostasis associated with excitotoxicity. The present study provides a new link between excitotoxicity, ER Ca2+ homeostasis, and the ER proteome.

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Dossat, A. M., Trychta, K. A., Fortuno, L. V., Richie, C. T., Harvey, B. K.. 2023-09-05. Excitotoxic glutamate levels cause the secretion of resident endoplasmic reticulum proteins. https://doi.org/10.1101/2023.09.03.556116

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