2012年10月31日 讯 /生物谷BIOON/ --近日,乔治亚州佐治亚州健康科学大学医学院神经科学家证实两种蛋白质的结合能使对学习和记忆至关重要的大脑受体不仅获得表达,同时也有助保持这些受体保留在所需要的地方。
NMDA受体能增加脑细胞的活性和脑细胞之间的交流,NMDA受体就像一个接收端,在脑细胞交流中发挥关键作用。在脑退化疾病如阿尔茨海默氏病和帕金森氏症中,NMDA受体是治疗靶点。
研究人员已经发现有助于稳定细胞表面受体的支架蛋白(scaffolding protein)SAP102,结合NMDA受体亚单位GluN2B两个位点。佐治亚州健康科学大学医学院的乔治亚州的神经科学家Bo-Shiun Chen表示:一个结合位点参与稳定细胞表面上的受体,另一个位点在清除受体中是很重要的。以前,研究人员从来没有想过相同的支架蛋白会有两个角色,相关研究结果发表在Cell Reports杂志上。
科学家相信通过了解这些受体功能的正常转化,可以更多了解如何防止如老年痴呆症等疾病。有趣的是,这个关键蛋白质SAP102,是骨架蛋白MAGUK家庭成员中唯一直接促发疾病的蛋白,它的突变会导致智力残疾。虽然所有的细胞在其表面上存在一个受体数量监管系统,但在阿尔茨海默氏症中,受体往往会加速消逝,如此神经元与神经元的沟通也减少。
研究发现神经递质谷氨酸有助于建立和维护突触,并有助于GluN2B与突触结合。事实上,这些受体的数目随着年龄的增长而降低,这可能是青少年学习起来更容易的原因之一。(生物谷:Bioon.com)
doi:10.1016/j.celrep.2012.09.024
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SAP102 Mediates Synaptic Clearance of NMDA Receptors
Bo-Shiun Chen, John A. Gray, Antonio Sanz-Clemente, Zhe Wei, Eleanor V. Thomas, Roger A. Nicoll, Katherine W. Roche.
Membrane-associated guanylate kinases (MAGUKs) are the major family of scaffolding proteins at the postsynaptic density. The PSD-MAGUK subfamily, which includes PSD-95, PSD-93, SAP97, and SAP102, is well accepted to be primarily involved in the synaptic anchoring of numerous proteins, including N-methyl-D-aspartate receptors (NMDARs). Notably, the synaptic targeting of NMDARs depends on the binding of the PDZ ligand on the GluN2B subunit to MAGUK PDZ domains, as disruption of this interaction dramatically decreases NMDAR surface and synaptic expression. We recently reported a secondary interaction between SAP102 and GluN2B, in addition to the PDZ interaction. Here, we identify two critical residues on GluN2B responsible for the non-PDZ binding to SAP102. Strikingly, either mutation of these critical residues or knockdown of endogenous SAP102 can rescue the defective surface expression and synaptic localization of PDZ binding-deficient GluN2B. These data reveal an unexpected, nonscaffolding role for SAP102 in the synaptic clearance of GluN2B-containing NMDARs.