Restoration of Sarco/Endoplasmic Reticulum Ca2+-ATPase Activity Functions as a Pivotal Therapeutic Target of Anti-Glutamate-Induced Excitotoxicity to Attenuate Endoplasmic Reticulum Ca2+ Depletion

Abstract

Glutamate-induced excitotoxicity is a pathological basis of many acute/chronic neurodegenerative diseases. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2b) is a membrane-embedded P-type ATPase pump that manages the translocation of calcium ions (Ca2+) from cytosol into the lumen of the endoplasmic reticulum (ER) calcium stores. It participates in a wide range of biological functions in the central nervous system (CNS). However, the role of SERCA2b in glutamate-induced excitotoxicity and its mechanism must be elucidated. Herein, we demonstrate that SERCA2b mutants exacerbate the excitotoxicity of hypo-glutamate stimulation on HT22 cells. In this study, SERCA2b mutants accelerated Ca2+ depletion through loss-of-function (reduced pumping capacity) or gain-of-function (acquired leakage), resulting in ER stress. In addition, the occurrence of ER Ca2+ depletion increased mitochondria-associated membrane formation, which led to mitochondrial Ca2+ overload and dysfunction. Moreover, the enhancement of SERCA2b pumping capacity or inhibition of Ca2+ leakage attenuated Ca2+ depletion and impeded excitotoxicity in response to hypo-glutamate stimulation. In conclusion, SERCA2b mutants exacerbate ER Ca2+-depletion-mediated excitotoxicity in glutamate-sensitive HT22 cells. The mechanism of disruption is mainly related to the heterogeneity of SERCA2b mutation sites. Stabilization of SRECA2b function is a critical therapeutic approach against glutamate-induced excitotoxicity. These data will expand understanding of organelle regulatory networks and facilitate the discovery and creation of drugs against excitatory/inhibitory imbalance in the CNS.

Subchronic Neurotoxic Effects of Cypermethrin on Earthworms

“…Given that the abnormal Ca 2+ distribution inside and outside the nerve membrane of earthworms triggered by cypermethrin exposure may be a possible mechanism leading to neurobehavioral changes such as cognitive de cits in earthworms, and Ca 2+ -ATP is one of the main enzymes determining the Ca 2+ distribution inside and outside the nerve membrane of earthworms, the Ca 2+ -ATPase was chosen as the receptor for molecular docking to explore the molecular mechanism of the neurotoxicity of cypermethrin in earthworms (Colina et al, 2002;Qi et al, 2021;Zhang et al, 2022).…”

Regulación del calcio por SERC-A antes de la enfermedad de Alzheimer y durante la misma

“…Este resultado se ha obtenido también en células HEK, HeLa y BMGK expuestas a tapsigargina y peróxido de hidrógeno, como inductores de estrés del retículo endoplásmico cuando se usa CDN1163 (47)(48)(49). De igual manera, al proporcionar el fármaco a ratas mutantes de SERC-A, que en un principio aceleraron la pérdida de Ca 2+ por excitotoxicidad inducida por glutamato (un neurotransmisor estimulante de los canales NMDA), se logró atenuar el estrés del retículo endoplásmico por agotamiento del ion (50). Por tanto, la estrategia terapéutica es clara: la activación de la SERC-A con CDN1163 o similares rellenará las reservas de Ca 2+ , aliviando el estrés del retículo endoplásmico, y rescatará eficazmente a las neuronas lesionadas de la apoptosis.…”

Xingnaojing injection alleviates cerebral ischemia/reperfusion injury through regulating endoplasmic reticulum stress in Vivo and in Vitro

“…In addition, after acute ischemic stroke, the brain tissue in the lesion area is in a state of ischemia and hypoxia due to insufficient blood supply. The free radical content in the lesion tissue is significantly increased, affecting the calcium pump function on the endoplasmic reticulum membrane, thus gradually exhausting Ca 2+ in the endoplasmic reticulum and causing calcium overload in cytoplasm and mitochondria, which further induce ERS, causing cell apoptosis [ 23 , 24 ]. Thus, down-regulating apoptosis through suppressing ERS is a significant approach for alleviating cerebral ischemia/reperfusion injury.…”