Intracellular Metabotropic Glutamate Receptor 5 (mGluR5) Activates Signaling Cascades Distinct from Cell Surface Counterparts
Intracellular Metabotropic Glutamate Receptor 5 (mGluR5) Activates Signaling Cascades Distinct from Cell Surface Counterparts
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DOI：
10.1074/jbc.m109.046276
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发表时间：
2009-12-18
影响因子：
4.8
通讯作者：
O'Malley, Karen L.
中科院分区：
文献类型：
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作者：
Jong, Yuh-Jiin I.;Kumar, Vikas;O'Malley, Karen L.
G蛋白偶联受体被认为是将细胞外信号从其在细胞表面的位置传递到细胞质。一些受体，包括代谢型谷氨酸受体5（mGluR 5），也在细胞内膜上高度表达，在那里它们发挥未知的功能。在这里，我们表明，细胞表面与细胞内mGluR 5的激活导致独特的Ca 2+签名，导致独特的细胞反应。具体而言，细胞表面或细胞内mGluR 5的活化导致JNK、Ca 2 +/钙调蛋白依赖性蛋白激酶（CaMK）和环腺苷3 '，5'-单磷酸响应元件结合蛋白磷酸化，而仅细胞内mGluR 5的活化导致ERK 1/2和Elk-1磷酸化。使用药理学和遗传学方法，本研究结果支持CaMK激酶在介导mGluR 5依赖性环腺苷3 '，5'-单磷酸响应元件结合蛋白磷酸化中的作用，而CaMK II是细胞内mGluR 5介导的Elk-1磷酸化的上游。与显示Elk-1调节基因表达级联的模型一致，已知的Elk-1靶点c-fos和egr 1在细胞内mGluR 5激活后上调，而代表性的非Elk-1靶点c-jun则没有。这些发现强调谷氨酸不仅作为细胞表面受体的神经递质，而且当转运到细胞中时，还可以激活细胞内受体，如mGluR 5。细胞内mGluR 5的谷氨酸激活在调节细胞核Ca 2+、转录激活和生理过程如突触可塑性所必需的基因表达中起重要作用。
G-protein-coupled receptors are thought to transmit extracellular signals to the cytoplasm from their position on the cell surface. Some receptors, including the metabotropic glutamate receptor 5 (mGluR5), are also highly expressed on intracellular membranes where they serve unknown functions. Here, we show that activation of cell surface versus intracellular mGluR5 results in unique Ca2+ signatures leading to unique cellular responses. Specifically, activation of either cell surface or intracellular mGluR5 leads to JNK, Ca2+/calmodulin-dependent protein kinase (CaMK), and cyclic adenosine 3',5'-monophosphate-responsive element-binding protein phosphorylation, whereas activation of only intracellular mGluR5 leads to ERK1/2 and Elk-1 phosphorylation. Using pharmacological and genetic approaches, the present findings support a role for CaMK kinase in mediating mGluR5-dependent cyclic adenosine 3',5'-monophosphate-responsive element-binding protein phosphorylation, whereas CaMKII is upstream of intracellular mGluR5-mediated Elk-1 phosphorylation. Consistent with models showing Elk-1 regulating cascades of gene expression, the known Elk-1 targets c-fos and egr1 were up-regulated following intracellular mGluR5 activation, whereas a representative non-Elk-1 target, c-jun, was not. These findings emphasize that glutamate not only serves as a neurotransmitter for cell surface receptors but, when transported into the cell, can also activate intracellular receptors such as mGluR5. Glutamate activation of intracellular mGluR5 serves an important role in the regulation of nuclear Ca2+, transcriptional activation, and gene expression necessary for physiological processes such as synaptic plasticity.