Activity-Dependent Proteolytic Cleavage of Neuroligin-1
Activity-Dependent Proteolytic Cleavage of Neuroligin-1
复制标题
DOI：
10.1016/j.neuron.2012.10.003
复制
发表时间：
2012-10-18
期刊：
影响因子：
16.2
通讯作者：
Iwatsubo, Takeshi
中科院分区：
文献类型：
--
作者：
Suzuki, Kunimichi;Hayashi, Yukari;Iwatsubo, Takeshi
神经连接素（NLG）是一种突触后粘附分子，通过与突触前配体neurexin结合参与突触的形成。在这里，我们报告，神经连接素-1（NLG 1）经历胞外域脱落在atmamembrane柄区域产生的分泌形式的NLG 1和膜栓系的C-末端片段（CTF）在成年大鼠大脑在体内以及在神经元培养。药理学和遗传学研究确定ADAM 10作为负责NLG 1脱落的主要蛋白酶，后者通过突触NMDA受体激活或与可溶性neurexin配体相互作用而增强。NLG 1-CTF随后被早老素/γ-分泌酶切割。可溶性NLG 1的分泌显着上调下一个长期的癫痫发作条件下，和NLG 1脱落的抑制导致神经元培养物中的树突棘的数量增加。总的来说，NLG 1的神经元活性依赖性蛋白水解加工可以负调节兴奋性突触处的棘的重塑。
Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/gamma-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.