Piguel Nicolas H, Fievre Sabine, Blanc Jean-Michel, Carta Mario, Moreau Maïté M, Moutin Enora, Pinheiro Vera L, Medina Chantal, Ezan Jerome, Lasvaux Léa, Loll François, Durand Christelle M, Chang Kai, Petralia Ronald S, Wenthold Robert J, Stephenson F Anne, Vuillard Laurent, Darbon Hervé, Perroy Julie, Mulle Christophe, Montcouquiol Mireille, Racca Claudia, Sans Nathalie
Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
Institut Interdisciplinaire de Neurosciences, University of Bordeaux, UMR 5297, 33000 Bordeaux, France; Institut Interdisciplinaire de Neurosciences, CNRS, UMR 5297, 33000 Bordeaux, France.
Cell Rep. 2014 Oct 23;9(2):712-27. doi: 10.1016/j.celrep.2014.09.017. Epub 2014 Oct 9.
The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.
谷氨酸受体向突触的适当运输对于基本突触功能和突触可塑性至关重要。现在人们已经认识到，NMDA受体（NMDARs）会内化并在质膜上循环利用，而且还会在突触和突触外池之间交换；这些NMDAR特性也是控制突触可塑性的关键。Scribble1是一种大型PDZ蛋白，是突触形成和突触可塑性所必需的。在此，我们表明Scribble1的水平以活动依赖的方式受到调节，并且Scribble1控制质膜上NMDARs的数量。值得注意的是，Scribble1通过在NMDAR激活后增加GluN2A亚基向质膜的循环利用，防止其进行溶酶体运输和降解。最后，我们表明Scribble1上的一个特定YxxR基序通过与AP2的直接相互作用来控制这些机制。总之，我们的研究结果确定了一种通过Scribble1复合信号控制突触NMDAR水平的分子机制。
