Ca(2+) ions play a fundamental role in cell death mediated by oxidative glutamate toxicity or oxytosis, a form of programmed cell death similar and possibly identical to other forms of cell death like ferroptosis. Ca(2+) influx from the extracellular space occurs late in a cascade characterized by depletion of the intracellular antioxidant glutathione, increases in cytosolic reactive oxygen species and mitochondrial dysfunction. Here, we aim to compare oxidative glutamate toxicity with ferroptosis, address the signaling pathways that culminate in Ca(2+) influx and cell death and discuss the proteins that mediate this. Recent evidence hints toward a role of the machinery responsible for store-operated Ca(2+) entry (SOCE), which refills the endoplasmic reticulum (ER) after receptor-mediated ER Ca(2+) release or other forms of store depletion. Pharmacological inhibition of SOCE or transcriptional downregulation of proteins involved in SOCE like the ER Ca(2+) sensor STIM1, the plasma membrane Ca(2+) channels Orai1 and TRPC1 and the linking protein Homer protects against oxidative glutamate toxicity and direct oxidative stress caused by hydrogen peroxide or 1-methyl-4-phenylpyridinium (MPP+) injury, a cellular model of Parkinson's disease. This suggests that SOCE inhibition might have some potential therapeutic effects in human disease associated with oxidative stress like neurodegenerative disorders.
|Number of pages||9|
|Early online date||12-May-2017|
|Publication status||Published - Mar-2018|
- Journal Article