期刊
NEUROBIOLOGY OF DISEASE
卷 46, 期 1, 页码 109-117出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.12.051
关键词
Calcium dysregulation; NMDA receptor; Na+/Ca2+ exchanger; Glutamate; Neuron; Excitotoxicity
资金
- NIH/NINDS [R01 NS 050131]
- Indiana State Department of Health Indiana Spinal Cord and Brain Injury [A70-0-079212]
- Ralph W. and Grace M. Showalter foundation
- AHA (Midwest Affiliate) [10PRE4300005]
Glutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl-D-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and NCXrev contribute to glutamate-induced DCD is uncertain. Here, we show that both NMDAR and NCXrev are critical for DCD in neurons exposed to excitotoxic glutamate. In rat cultured hippocampal neurons, 25 mu M glutamate produced DCD accompanied by sustained increase in cytosolic Na+ ([Na+](c)) and plasma membrane depolarization. MK801 and memantine, noncompetitive NMDAR inhibitors, added shortly after glutamate, completely prevented DCD whereas AP-5, a competitive NMDAR inhibitor, failed to protect against DCD. None of the tested inhibitors lowered elevated [Na+](c), or restored plasma membrane potential. In the experiments with NCX reversal by gramicidin, MK801 and memantine robustly inhibited NCXrev while AP-5 was much less efficacious. In electrophysiological patch-clamp experiments MK801 and memantine inhibited NCXrev-mediated ion currents whereas AP-5 failed. Thus. MK801 and memantine, in addition to NMDAR, inhibited NCXrev. Inhibition of NCXrev either with KB-R7943, or by collapsing Na+ gradient across the plasma membrane, or by inhibiting Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and thus preventing the increase in [Na+](c) failed to preclude DCD. However, NCXrev inhibition combined with NMDAR blockade by AP-5 completely prevented DCD. Overall, our data suggest that both NMDAR and NCXrev are essential for DCD in glutamate-exposed neurons and inhibition of individual mechanism is not sufficient to prevent calcium dysregulation. (C) 2012 Elsevier Inc. All rights reserved.
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