Dennexin peptides modeled after the homophilic binding sites of the neural cell adhesion molecule (NCAM) promote neuronal survival, modify cell adhesion and impair spatial learning
Dennexin peptides modeled after the homophilic binding sites of the neural cell adhesion molecule (NCAM) promote neuronal survival, modify cell adhesion and impair spatial learning
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DOI：
10.1016/j.ejcb.2010.07.007
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发表时间：
2010-11-01
影响因子：
6.6
通讯作者：
Berezin, Vladimir
中科院分区：
文献类型：
--
作者：
Kohler, Lene B.;Christensen, Claus;Berezin, Vladimir
神经细胞粘附分子（NCAM）介导的细胞粘附导致细胞内信号级联的激活，其导致细胞应答，例如神经突生长、神经元存活和与认知过程相关的突触活动的调节。NCAM胞外域的免疫球蛋白（IG）1-2-3片段的晶体结构揭示了NCAM嗜同性粘附的新机制。本研究探讨了NCAM致密拉链形成的生物学意义。两种肽，称为dennexinA和dennexinB，分别在晶体结构中观察到的Ig 1和Ig 3之间以及Ig 2和Ig 2之间的接触界面后建模。虽然这两个dennexin肽不同的氨基酸序列，他们都调制细胞粘附，反映了抑制NCAM介导的神经突起生长。这两种dennexins也促进神经元的存活，dennexinA的效果是独立的聚唾液酸的表达。与dennexinA在体外对NCAM介导的粘附的作用一致，该肽在Morris水迷宫测试中损害大鼠的长期记忆保持。因此，dennexins是一种新的位点特异性药理学工具，用于阐明NCAM在正常和病理条件下的各种生物过程中的作用。(C)2010年Elsevier GmbH。All rights reserved.
Neural cell adhesion molecule (NCAM)-mediated cell adhesion results in activation of intracellular signaling cascades that lead to cellular responses such as neurite outgrowth, neuronal survival, and modulation of synaptic activity associated with cognitive processes. The crystal structure of the immunoglobulin (Ig) 1-2-3 fragment of the NCAM ectodomain has revealed novel mechanisms for NCAM homophilic adhesion. The present study addressed the biological significance of the so called dense zipper formation of NCAM. Two peptides, termed dennexinA and dennexinB, were modeled after the contact interfaces between Ig1 and Ig3 and between Ig2 and Ig2, respectively, observed in the crystal structure. Although the two dennexin peptides differed in amino acid sequence, they both modulated cell adhesion, reflected by inhibition of NCAM-mediated neurite outgrowth. Both dennexins also promoted neuronal survival, and the effect of dennexinA was independent of polysialic acid expression. Consistent with the effect of dennexinA on NCAM-mediated adhesion in vitro, the peptide impaired long-term memory retention in rats in the Morris water maze test. Thus, dennexins are novel site-specific pharmacological tools for elucidation of the role of NCAM in a variety of biological processes under normal and pathological conditions. (C) 2010 Elsevier GmbH. All rights reserved.