Differential roles for NSF and GRIP/ABP in AMPA receptor cycling
Differential roles for NSF and GRIP/ABP in AMPA receptor cycling
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DOI：
10.1073/pnas.102156099
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Malenka, RC
中科院分区：
文献类型：
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作者：
Braithwaite, SP;Xia, HH;Malenka, RC
Alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic酸受体(AM-PAR)在突触上的稳定性和运动性是控制突触强度的重要因素。在这里，我们研究了与GluR2亚基相互作用的N-乙基马来酰亚胺敏感融合蛋白(NSF)、谷氨酸受体AMPAR结合蛋白(ABP)相互作用蛋白(GRIP)/(ABP)以及与C-激酶-1相互作用的蛋白(PICK1)在调控AMPAR表面表达和循环中的作用。表位标记的GluR2形成功能性受体，显示出针对突触位置的靶向。与NSF、PDZ蛋白(GRIP/ABP和PICK1)或单独与GRIP/ABP结合的构建体均表现出正常的表面靶向和构造性循环。然而，缺乏NSF结合导致受体内吞的程度高于野生型受体，以响应AMPA或N-甲基-D-天冬氨酸(NMDA)的应用。相反，不能与GRIP/ABP结合的GluR2突变体的行为表明，这些PDZ蛋白在稳定细胞内因刺激而内化的AMPAR池中发挥作用，从而抑制它们循环到突触膜上。这些结果为GluR2相互作用蛋白在AMPAR运输中的不同功能作用提供了进一步的证据。
alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AM PAR) stability and movement at synapses are important factors controlling synaptic strength. Here, we study the roles of proteins [N-ethylmaleimide-sensitive fusion protein (NSF), glutamate receptor AMPAR binding protein (ABP)-interacting protein (GRIP)/(ABP), and protein interacting with C-kinase-1 (PICK1) that interact with the GluR2 subunit in the control of the surface expression and cycling of AMPARs. Epitope-tagged GluR2 formed functional receptors that exhibited targeting to synaptic sites. Constructs in which binding to NSF, PDZ proteins (GRIP/ABP and PICK1), or GRIP/ABP alone was eliminated each exhibited normal surface targeting and constitutive cycling. The lack of NSF binding, however, resulted in receptors that were endocytosed to a greater extent than wild-type receptors in response to application of AMPA or N-methyl-D-aspartate (NMDA). Conversely, the behavior of the GluR2 mutants incapable of binding to GRIP/ABP suggests that these PDZ proteins play a role in the stabilization of an intracellular pool of AMPARs that have been internalized on stimulation, thus inhibiting their recycling to the synaptic membrane. These results provide further evidence for distinct functional roles of GluR2-interacting proteins in AMPAR trafficking.