Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices
Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices
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DOI：
10.1016/j.neuint.2004.07.002
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Baudry, M
中科院分区：
文献类型：
--
作者：
Jourdi, H;Yanagihara, T;Baudry, M
AMPA 受体 (AMPAr) 的正调节剂（AMPAr）也称为 ampakines，是受体的变构效应物，由于其可用于治疗各种中枢神经系统疾病和疾病（如轻度认知障碍、精神分裂症和阿尔茨海默病），因此在过去几年中得到了广泛的研究。安帕金已被证明可以提高动物和人类受试者的记忆任务表现。这种效应与它们通过 AMPAr 增加激动剂介导的离子流入的能力有关。从而增强突触反应并促进谷氨酸能突触的长时程增强（LTP）诱导。由于 LTP 与钙蛋白酶激活和血影蛋白降解相关，因此我们确定了安帕金处理培养的海马切片对血影蛋白降解的影响。通过测定血影蛋白 145-150 kDa 降解产物的水平来评估钙蛋白酶活化。我们的数据表明，海马切片与一些（但不是全部）AMPA 受体正调节剂一起孵育会导致血影蛋白降解增强，而钙蛋白酶抑制剂可阻断这种作用。此外。 AMPAr 拮抗剂而非 NMDAr 拮抗剂可阻断安帕金诱导的血影蛋白降解。这些结果表明，长期使用选定的安帕金治疗会导致血影蛋白降解，这是由钙依赖性蛋白酶钙蛋白酶激活介导的。 (C) 2004 Elsevier Ltd. 保留所有权利。
Positive modulators of AMPA receptors (AMPAr), also known as ampakines, are allosteric effectors of the receptors and have been extensively studied in past years due to their potential use as treatment for various diseases and ailments of the central nervous system such as mild cognitive impairment, schizophrenia, and Alzheimer's disease. Ampakines have been shown to improve performance on memory tasks in animals and in human subjects. an effect linked to their ability to increase agonist-mediated ion influx through AMPAr. thus leading to enhanced synaptic responses and facilitation of long-term potentiation (LTP) induction at glutamatergic synapses. As LTP is associated with calpain activation and spectrin degradation, we determined the effects of ampakine treatment of cultured hippocampal slices on spectrin degradation. Calpain activation was evaluated by determining the levels of the 145-150 kDa degradation products of Spectrin. Our data indicated that incubation of hippocampal slices with some, but not all positive modulators of AMPA receptors resulted in enhanced spectrin degradation, an effect that was blocked by a calpain inhibitor. In addition. an antagonist of AMPAr but not of NMDAr blocked ampakine-induced spectrin degradation. These results indicate that prolonged treatment with selected ampakines leads to spectrin degradation mediated by activation of the calcium-dependent protease calpain. (C) 2004 Elsevier Ltd. All rights reserved.