Sossa K G, Court B L, Carroll R C
Department of Neuroscience, Rose Kennedy Center for Mental Retardation, 1410 Pelham Parkway, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mol Cell Neurosci. 2006 Mar;31(3):574-85. doi: 10.1016/j.mcn.2005.11.011. Epub 2006 Jan 10.
AMPA receptor (AMPAR) trafficking at CNS synapses is regulated by several receptor-binding proteins. One model of AMPAR endocytosis entails the cotargeting of the GluR2-interacting protein PICK1 and activated PKC to synapses. We demonstrate that NMDA receptor (NMDAR) activation mediates bidirectional changes in surface AMPARs through two additional forms of PICK1 redistribution. In neurons, NMDAR activation, which induces AMPAR endocytosis, increases endosomal PICK1 clustering. In contrast, stronger NMDAR activation rapidly reduces PICK1 clustering accompanied by decreases in PICK1/GluR2 association and increases in surface AMPAR levels. PICK1-siRNA similarly increases surface AMPARs and occludes the NMDAR-mediated effect, demonstrating the role of PICK1 in this process. Bidirectional NMDAR-mediated changes in PICK1 localization are determined by the magnitude of receptor-activated dendritic calcium signals. Our results show that PICK1 localization in dendrites is subject to multiple forms of regulation that contribute to surface AMPAR expression, likely by modulating the numbers of AMPARs maintained in intracellular compartments.
中枢神经系统（CNS）突触处的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）转运受多种受体结合蛋白调控。AMPAR内吞作用的一种模型涉及与GluR2相互作用的蛋白PICK1和活化的蛋白激酶C（PKC）共同靶向突触。我们证明，N-甲基-D-天冬氨酸受体（NMDAR）激活通过PICK1重新分布的另外两种形式介导表面AMPAR的双向变化。在神经元中，诱导AMPAR内吞作用的NMDAR激活会增加内体中PICK1的聚集。相反，更强的NMDAR激活会迅速减少PICK1聚集，同时伴随着PICK1/GluR2结合减少以及表面AMPAR水平增加。PICK1小干扰RNA（siRNA）同样会增加表面AMPAR，并阻断NMDAR介导的效应，证明了PICK1在此过程中的作用。NMDAR介导的PICK1定位双向变化由受体激活的树突状钙信号强度决定。我们的结果表明，树突中PICK1的定位受到多种形式的调控，这些调控可能通过调节细胞内区室中维持的AMPAR数量来影响表面AMPAR的表达。
