Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
J Neurochem. 2013 Dec;127(5):620-31. doi: 10.1111/jnc.12434. Epub 2013 Sep 17.
Two glutamate receptors, metabotropic glutamate receptor 5 (mGluR5), and ionotropic NMDA receptors (NMDAR), functionally interact with each other to regulate excitatory synaptic transmission in the mammalian brain. In exploring molecular mechanisms underlying their interactions, we found that Ca(2+) /calmodulin-dependent protein kinase IIα (CaMKIIα) may play a central role. The synapse-enriched CaMKIIα directly binds to the proximal region of intracellular C terminal tails of mGluR5 in vitro. This binding is state-dependent: inactive CaMKIIα binds to mGluR5 at a high level whereas the active form of the kinase (following Ca(2+) /calmodulin binding and activation) loses its affinity for the receptor. Ca(2+) also promotes calmodulin to bind to mGluR5 at a region overlapping with the CaMKIIα-binding site, resulting in a competitive inhibition of CaMKIIα binding to mGluR5. In rat striatal neurons, inactive CaMKIIα constitutively binds to mGluR5. Activation of mGluR5 Ca(2+) -dependently dissociates CaMKIIα from the receptor and simultaneously promotes CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα-sensitive site. Together, the long intracellular C-terminal tail of mGluR5 seems to serve as a scaffolding domain to recruit and store CaMKIIα within synapses. The mGluR5-dependent Ca(2+) transients differentially regulate CaMKIIα interactions with mGluR5 and GluN2B in striatal neurons, which may contribute to cross-talk between the two receptors. We show that activation of mGluR5 with a selective agonist triggers intracellular Ca(2+) release in striatal neurons. Released Ca(2+) dissociates preformed CaMKIIα from mGluR5 and meanwhile promotes active CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα-sensitive site. This agonist-induced cascade seems to mediate crosstalk between mGluR5 and NMDA receptors in neurons.
两种谷氨酸受体，代谢型谷氨酸受体 5（mGluR5）和离子型 NMDA 受体（NMDAR），在功能上相互作用，调节哺乳动物大脑中的兴奋性突触传递。在探索它们相互作用的分子机制时，我们发现钙/钙调蛋白依赖性蛋白激酶 IIα（CaMKIIα）可能发挥核心作用。突触丰富的 CaMKIIα 可在体外直接与 mGluR5 细胞内 C 端尾部的近段结合。这种结合是状态依赖的：无活性的 CaMKIIα 以高水平与 mGluR5 结合，而激酶的活性形式（在 Ca2+/钙调蛋白结合和激活后）则失去与受体的亲和力。Ca2+ 还促进钙调蛋白与 mGluR5 结合在与 CaMKIIα 结合位点重叠的区域，导致 CaMKIIα 与 mGluR5 结合的竞争性抑制。在大鼠纹状体神经元中，无活性的 CaMKIIα 持续与 mGluR5 结合。mGluR5 的 Ca2+依赖性激活使 CaMKIIα 从受体上解离，并同时促进 CaMKIIα 与相邻的 NMDAR GluN2B 亚基结合，使 CaMKIIα 能够在 CaMKIIα 敏感位点磷酸化 GluN2B。总的来说，mGluR5 的长细胞内 C 端尾巴似乎充当一个支架结构域，将 CaMKIIα 招募到突触中并储存起来。mGluR5 依赖性 Ca2+瞬变差异调节纹状体神经元中 CaMKIIα 与 mGluR5 和 GluN2B 的相互作用，这可能有助于两种受体之间的串扰。我们发现，选择性激动剂激活 mGluR5 会在纹状体神经元中引发细胞内 Ca2+释放。释放的 Ca2+使预形成的 CaMKIIα 与 mGluR5 解离，同时促进活性 CaMKIIα 与相邻的 NMDAR GluN2B 亚基结合，使 CaMKIIα 能够在 CaMKIIα 敏感位点磷酸化 GluN2B。这种激动剂诱导的级联反应似乎介导了神经元中 mGluR5 和 NMDA 受体之间的串扰。
