Intracellular calcium plays a critical role in the alcohol-mediated death of cerebellar granule neurons Journal Article

Authors: Kouzoukas, D. E.; Li, G; Takapoo, M.; Moninger, T.; Bhalla, R. C.; Pantazis, N. J.
Article Title: Intracellular calcium plays a critical role in the alcohol-mediated death of cerebellar granule neurons
Abstract: Alcohol is a potent neuroteratogen that can trigger neuronal death in the developing brain. However, the mechanism underlying this alcohol-induced neuronal death is not fully understood. Utilizing primary cultures of cerebellar granule neurons (CGN), we tested the hypothesis that the alcohol-induced increase in intracellular calcium [Ca(2+)](i) causes the death of CGN. Alcohol induced a dose-dependent (200-800 mg/dL) neuronal death within 24 h. Ratiometric Ca(2+) imaging with Fura-2 revealed that alcohol causes a rapid (1-2 min), dose-dependent increase in [Ca(2+)](i), which persisted for the duration of the experiment (5 or 7 min). The alcohol-induced increase in [Ca(2+)](i) was observed in Ca(2+) -free media, suggesting intracellular Ca(2+) release. Pre-treatment of CGN cultures with an inhibitor (2-APB) of the inositol-triphosphate receptor (IP(3) R), which regulates Ca(2+) release from the endoplasmic reticulum (ER), blocked both the alcohol-induced rise in [Ca(2+)](i) and the neuronal death caused by alcohol. Similarly, pre-treatment with BAPTA/AM, a Ca(2+) -chelator, also inhibited the alcohol-induced surge in [Ca(2+) ](i) and prevented neuronal death. In conclusion, alcohol disrupts [Ca(2+)](i) homeostasis in CGN by releasing Ca(2+) from intracellular stores, resulting in a sustained increase in [Ca(2+)](i). This sustained increase in [Ca(2+)](i) may be a key determinant in the mechanism underlying alcohol-induced neuronal death.
Journal Title: Journal of neurochemistry
Volume: 124
Issue: 3
ISSN: 1471-4159; 0022-3042
Publisher: International Society for Neurochemistry  
Journal Place: England
Date Published: 2013
Start Page: 323
End Page: 335
Language: ENG
Notes: LR: 20161108; CI: (c) 2012; GR: R01 AA011577/AA/NIAAA NIH HHS/United States; GR: AA011577/AA/NIAAA NIH HHS/United States; JID: 2985190R; 0 (Central Nervous System Depressants); 0 (Culture Media); 3K9958V90M (Ethanol); SY7Q814VUP (Calcium); NIHMS419319; 2012/04/06 [received]; 2012/09/30 [revised]; 2012/10/10 [accepted]; ppublish