Structure function and splice site analysis of the synaptogenic activity of the neurexin-1β LNS domain

被引:128
作者
Graf, ER
Kang, Y
Hauner, AM
Craig, AM
机构
[1] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA
[2] Univ British Columbia, Brain Res Ctr, Vancouver, BC V6T 2B5, Canada
[3] Univ British Columbia, Dept Psychiat, Vancouver, BC V6T 2B5, Canada
[4] Korea Univ, Coll Med, Dept Anat, Seoul 136701, South Korea
[5] Korea Univ, Coll Med, Div Brain Korea Biomed Sci 21, Seoul 136701, South Korea
关键词
synaptogenesis; neuroligin; glutamate; GABA; gephyrin; PSD-95; postsynaptic;
D O I
10.1523/JNEUROSCI.1253-05.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Recent findings suggest that the neurexin-neuroligin link promotes both GABAergic and glutamatergic synaptogenesis, but the mechanism by which neurexins influence the clustering of appropriate neuroligins and postsynaptic differentiation remains unclear. Previous studies suggested that the presence or absence of alternatively spliced residues at splice site 4 (S4) in the neurexin LNS domain may regulate neurexin function. We demonstrate that addition of the S4 insert selectively reduces the ability of neurexin-1 beta to cluster neuroligin-1/3/4 and glutamatergic postsynaptic proteins, although clustering of neuroligin-2 and GABAergic postsynaptic proteins remain strong. Furthermore, addition of the S4 insert decreases the binding affinity of neurexin-1 beta to neuroligins-1 and -4 but has little effect on binding to neuroligins-2 and -3. Additional structure- function studies reveal the neurexin binding interface mediating synaptogenic activity to be composed primarily of residues in the beta 2 beta 3, beta 6 beta 7, and beta 10 beta 11 loops on one rim of the LNS domain beta sandwich. Mutation of two predicted Ca2+-binding residues disrupts postsynaptic protein clustering and binding to neuroligins, consistent with previous findings that neurexin-neuroligin binding is Ca2+ dependent. Glutamatergic postsynaptic clustering was more readily disrupted by the mutagenesis than GABAergic postsynaptic protein clustering. Perhaps neurexins-neuroligins, or neurexin-1 beta at least, is most important for GABA synapse formation or controlling the balance of GABA and glutamate synapses. These results suggest that differential neurexin-neuroligin binding affinities and splice variations may play an instructive role in postsynaptic differentiation.
引用
收藏
页码:4256 / 4265
页数:10
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