A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes

被引:89
作者
Dong, E [1 ]
Caruncho, H [1 ]
Liu, WS [1 ]
Smalheiser, NR [1 ]
Grayson, DR [1 ]
Costa, E [1 ]
Guidotti, A [1 ]
机构
[1] Univ Illinois, Inst Psychiat, Dept Psychiat, Coll Med, Chicago, IL 60612 USA
关键词
D O I
10.1073/pnas.1031602100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Reelin is synthesized and secreted into extracellular matrix by cortical gamma-aminobutyric acid (GABA)ergic interneurons and binds with high affinity to the extracellular domain of integrin receptors expressed in dendritic shaft and spine postsynaptic densities (DSPSD) of pyramidal neurons. In heterozygous reeler mice, reelin bound to DSPSD, and the expression of Arc (activity-regulated cytoskeletal protein) is lower than in wild-type mice. We studied the effect of reelin on Arc and total protein synthesis in synapto-neurosomes (SNSs) prepared from mouse neocortex. Recombinant full-length mouse reelin displaces the high affinity (K-D = 60 fM) binding of [I-125]echistatin (a competitive integrin receptor antagonist) to integrin receptors with a K-i of 22 pM and with a Hill slope close to 1. Echistatin (50-100 nM) competitively antagonizes and abates reelin binding. The addition of reelin (2-40 pM) to SNSs enhances the incorporation of [S-35]methionine into Arc and other rapidly translated proteins in a concentration-dependent manner. This incorporation is virtually abolished by 50-100 nM echistatin or by 5-10 nM rapamycin, a blocker of the mammalian target of rapamycin kinase. We conclude that reelin binds with high affinity to integrin receptors expressed in SNSs and thereby activates Arc protein synthesis.
引用
收藏
页码:5479 / 5484
页数:6
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