Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit.
Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit.
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DOI：
10.1038/s41598-018-22542-z
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发表时间：
2018-03-07
影响因子：
4.6
通讯作者：
Hanley JG
中科院分区：
文献类型：
--
作者：
Parkinson GT;Chamberlain SEL;Jaafari N;Turvey M;Mellor JR;Hanley JG
AMPA受体（AMPAR）的运输是突触强度和突触可塑性的关键决定因素。在基础条件下，组成性运输通过内化到内体系统中来维持表面AMPAR，其中大多数被分选并靶向再循环回质膜。NMDA受体（NMDAR）依赖性长期抑郁症（LTD）的特征在于突触强度的降低，并且涉及AMPAR从再循环途径到溶酶体的内体分选。确定AMPAR是否被运输到溶酶体或再循环内体，特别是响应于NMDAR刺激的机制尚不清楚。在这里，我们定义了肌动蛋白调节蛋白corpine作为AMPAR内体分选的介质与GluA 2亚基的直接相互作用的作用。破坏神经元中的GluA 2-coronin结合导致含GluA 2/A3受体靶向溶酶体及其随后的降解，导致基础条件下表面和突触GluA 2的损失以及随后LTD表达的闭塞。此外，我们表明，NMDAR刺激导致内源性cornea从GluA 2通过cornea的酪氨酸磷酸化的解离。这些结果表明，皮质醇通过引导受体远离溶酶体来维持GluA 2/A3水平，并且破坏GluA 2-皮质醇相互作用以将GluA 2/A3靶向溶酶体是LTD表达的重要组成部分。
AMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression.
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DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.7
作者：
Anggono V;Huganir RL
通讯作者：
Huganir RL
影响因子：
5.3
作者：
Fernandez-Monreal, Monica;Brown, Tyler C.;Esteban, Jose A.
通讯作者：
Esteban, Jose A.
DOI：
10.1523/jneurosci.5944-10.2011
发表时间：
2011-02-23
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lussier MP;Nasu-Nishimura Y;Roche KW
通讯作者：
Roche KW
影响因子：
4
作者：
Oser, Matthew;Mader, Christopher C.;Condeelis, John
通讯作者：
Condeelis, John