Endoplasmic Reticulum Ca(2+) Dysregulation And Endoplasmic Reticulum Stress Following In Vitro Neuronal Ischemia: Role Of Na(+)-K(+)-Cl(-) Cotransporter

JOURNAL OF NEUROCHEMISTRY(2008)

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Abstract
We investigated the role of Na(+)-K(+)-Cl(-) cotransporter (NKCC1) in conjunction with Na(+)/Ca(2+) exchanger (NCX) in disruption of endoplasmic reticulum (ER) Ca(2+) homeostasis and ER stress development in primary cortical neurons following in vitro ischemia. Oxygen-glucose deprivation (OGD) and reoxygenation (REOX) caused a rise in [Na(+)](cyt) which was accompanied by an elevation in [Ca(2+)](cyt). Inhibition of NKCC1 with its potent inhibitor bumetanide abolished the OGD/REOX-induced rise in [Na(+)](cyt) and [Ca(2+)](cyt). Moreover, OGD significantly increased Ca(ER)(2+) accumulation. Following REOX, a biphasic change in Ca(ER)(2+) occurred with an initial release of Ca(ER)(2+) which was sensitive to inositol 1,4,5-trisphosphate receptor (IP(3)R) inhibition and a subsequent refilling of Ca(ER)(2+) stores. Inhibition of NKCC1 activity with its inhibitor or genetic ablation prevented the release of Ca(ER)(2+). A similar result was obtained with inhibition of reversed mode operation of NCX (NCX(rev)). OGD/REOX also triggered a transient increase of glucose regulated protein 78 (GRP78), phospho-form of the alpha subunit of eukaryotic initiation factor 2 (p-eIF2 alpha), and cleaved caspase 12 proteins. Pre-treatment of neurons with NKCC1 inhibitor bumetanide inhibited upregulation of GRP78 and attenuated the level of cleaved caspase 12 and p-eIF2 alpha. Inhibition of NKCC1 reduced cytochrome C release and neuronal death. Taken together, these results suggest that NKCC1 and NCX(rev) may be involved in ischemic cell damage in part via disrupting ER Ca(2+) homeostasis and ER function.
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Key words
caspase 12,eukaryotic initiation factor 2 alpha,inositol 1,4,5-trisphosphate receptor,ischemia-reperfusion,oxygen and glucose deprivation,unfolded protein response
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