The role of SAP97 in synaptic glutamate receptor dynamics
The role of SAP97 in synaptic glutamate receptor dynamics
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DOI：
10.1073/pnas.0914422107
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发表时间：
2010-02-23
影响因子：
11.1
通讯作者：
Nicoll, Roger A.
中科院分区：
文献类型：
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作者：
Howard, MacKenzie A.;Elias, Guillermo M.;Nicoll, Roger A.
PSD-95样膜相关鸟苷酸激酶（PSD-MAGUK）家族的蛋白质对于将AMPA受体（AMPAR）运输到突触是至关重要的，这是基础突触传递和突触可塑性形式所必需的过程。突触相关蛋白97（SAP 97）表现出蛋白质相互作用，例如与GluA 1 AMPAR亚基的直接相互作用，以及在该蛋白质家族中独特的亚细胞定位（突触、突触周和树突）。部分由于SAP 97的种系敲除的致死性，该蛋白在突触传递和可塑性中的作用知之甚少。我们发现，SAP 97在早期发育过程中的过度表达将AMPAR和NMDA受体（NMDAR）运输到突触，并且SAP 97挽救了通常在PSD-93/-95双敲除神经元中观察到的AMPAR电流的缺陷。在整个发育过程中经历过SAP 97过表达的成熟神经元表现出增强的AMPAR和NMDAR电流，以及更快的NMDAR电流衰减动力学。在使用条件性SAP 97基因缺失的功能丧失实验中，我们没有记录到突触传递或长时程增强的缺陷。这些结果支持这样的假设，即SAP 97是转运谷氨酸受体并补偿敲除小鼠模型中其他PSD-MAGUK的机制的一部分。然而，由于功能冗余，当SAP 97在发育过程中被有条件地删除时，其他PSD-MAGUK可能会进行补偿。
Proteins of the PSD-95-like membrane-associated guanylate kinase (PSD-MAGUK) family are vital for trafficking AMPA receptors (AMPARs) to synapses, a process necessary for both basal synaptic transmission and forms of synaptic plasticity. Synapse-associated protein 97 (SAP97) exhibits protein interactions, such as direct interaction with the GluA1 AMPAR subunit, and subcellular localization (synaptic, perisynaptic, and dendritic) unique within this protein family. Due in part to the lethality of the germline knockout of SAP97, this protein's role in synaptic transmission and plasticity is poorly understood. We found that overexpression of SAP97 during early development traffics AMPARs and NMDA receptors (NMDARs) to synapses, and that SAP97 rescues the deficits in AMPAR currents normally seen in PSD-93/-95 double-knockout neurons. Mature neurons that have experienced the overexpression of SAP97 throughout development exhibit enhanced AMPAR and NMDAR currents, as well as faster NMDAR current decay kinetics. In loss-of-function experiments using conditional SAP97 gene deletion, we recorded no deficits in glutamatergic transmission or long-term potentiation. These results support the hypothesis that SAP97 is part of the machinery that traffics glutamate receptors and compensates for other PSD-MAGUKs in knockout mouse models. However, due to functional redundancy, other PSD-MAGUKs can presumably compensate when SAP97 is conditionally deleted during development.