Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.
Nat Neurosci. 2010 Oct;13(10):1199-207. doi: 10.1038/nn.2624. Epub 2010 Aug 29.
Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide-sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase- 2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.
AMPA 受体（AMPARs）的转运对于许多形式的突触可塑性很重要。然而，活动与由此产生的突触改变之间的联系尚不完全清楚。我们发现，参与膜融合事件和稳定表面 AMPAR 的 N-乙基马来酰亚胺敏感融合蛋白（NSF）与 Polo 样激酶-2（Plk2）之间存在直接相互作用，Plk2 是一种活性诱导激酶，可使兴奋性突触数量和强度呈同源性降低。Plk2 破坏了 NSF 与 AMPAR 的 GluA2 亚基的相互作用，促进了大鼠海马神经元表面 GluA2 的大量丢失，GluA2 与衔接蛋白 PICK1 和 GRIP1 的结合增加，以及突触 AMPAR 电流减少。这种机制需要 Plk2 与 NSF 的结合，而不是 Plk2 激酶活性，并且发生在 Plk2 蛋白中的一个模体中，该模体与典型的 Polo 盒相互作用位点无关。这些数据表明，增强的突触活动通过 Plk2 作用，通过 NSF 从 GluA2 的直接解离，导致表面 AMPAR 表达的同源性降低。
