Glutamate에 의한 세포내 칼슘농도변화와 세포독성과의 관계

황인영; 신임철; 송연숙; 성민제; 박혜지; 이윷모; 박철범; 이명구; 오기완; 심영용; 홍진태

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자료유형: 학술저널

저자정보: 황인영 신임철 송연숙 성민제 박혜지 이윷모 박철범 이명구 오기완 심영용 홍진태

저널정보: 한국독성학회 Toxicological Research Journal of Toxicology and Public Health Vol.18 No.4

발행연도: 2002.12

수록면: 355 - 362 (8page)

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Pathophysiological elevation of intracellular calcium concentration ([Ca^(2+)]_i) in the neuron has been considered as an important responsible factor in the neuronal cell damages. However, the mechanism of increase of [Ca^(2+)]_i and the relationship between [Ca^(2+)]_i level and cytotocixity have not been fully demonstrated. In the present study, real-time alteration of [Ca^(2+)]_i and cellular response (cell damages) in the pheochromocytoma cells (PC12) stimulated by glutamate were investigated. Glutamate dose dependently decreased cell viability determined propidium iodide fluorescence method and morphology change. Choversely related with cell damages, glutamate dose dependently increased the level of [Ca^(2+)]_i. To investigate the mechanism of glutamate-induced increase of [Ca^(2+)]_i, [Ca^(2+)]_i was first measured in the cells cultured in calcium free media and in the presence of dantrolene, an inhibitor of calcium release from ryanodine receptor located in endoplasmic reticulum (ER). Similar to the increase [Ca^(2+)]_i in the calcium-containing media, glutamate does dependently increased [Ca^(2+)]_i in the cells cultured in free calcium media. However, pretreatment (2hr) with 20~50μM dantrolene substantial lowered glutamate-induced increase of [Ca^(2+)]_i, suggesting that release of calcium from ER may be major sourse of increase of [Ca^(2+)]_i in PC12 cells. Dantrolene-induced inhibition of [Ca^(2+)]_i resulted in recovery of cytotoxicity by glutamate. Relevance of N-methyl-D-aspartate (NMDA) receptor, a type of glutamate receptor on glutamate-induced increase of [Ca^(2+)]_i, [Ca^(2+)]_i was also determined in the cells pretreated (2hr) with NMDA receptor antagonist MK-801. Glutamate-induced increase of [Ca^(2+)]_i was reduced by MK-801 dose dependently. Furthermore, glutamate-induced cytotoxicity was also provented by MK-801. These results demonstrate that glutamate increase [Ca^(2+)]_i dose dependently and thereby cause cytotoxicity. The increase of [Ca^(2+)]_i may release from ER, especially through ryanodine receptor and/or through NMDA receptor. Alteration of calcium homeostasis through disturbance of ER system and/or calaium influx through NMDA receptor could contribute glutamate-induced cell damages.

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