Functional Consequences of Nuclear mGlu5 Receptor Activation

描述（由申请人提供）：众所周知G蛋白偶联受体用于将细胞外信号转化为细胞内应答。然而，新出现的数据表明，一些受体主要位于细胞内膜上，在那里它们可能在细胞的生理学中发挥独特的作用。最近，我们已经表明，纹状体核膜上表达的mGlu5代谢型谷氨酸受体的激活导致快速，持续的核钙反应，可被受体特异性拮抗剂阻断。目前的结果表明，钠依赖性和非依赖性转运蛋白都参与移动激动剂穿过质膜和核膜，因为抑制任一转运系统会阻断激动剂诱导的核钙变化。值得注意的是，非转运激动剂诱导纹状体神经元快速，短暂的钙反应，而转运配体诱导长期，持续的钙平台。最后，核受体的配体刺激启动至少一个已知改变基因转录和调节突触可塑性的许多范例的信号级联。因为这些发现代表了从传统的模型强调细胞表面受体及其配体的根本出发，他们有重要的细胞分支的概念，即核受体可以调节核钙，以及在整个发展过程中的mGlu5特异性功能，并与突触可塑性。本申请的目标是利用我们建立的纹状体系统以及我们新表征的药理学工具来确定细胞内受体激活的长期后果。使用候选基因和无偏的基因组方法，我们将测试的主要假设，细胞表面与细胞内mGlu 5受体的激活导致基因表达的差异变化。由于mGlu5受体也参与各种神经变性和神经精神障碍如帕金森病、药物成瘾、焦虑和精神分裂症的病理生理学，因此它们代表了药物发现的有吸引力的靶标。未来的研究靶向药物细胞表面与细胞内受体可能会导致这些疾病的新的治疗工具。因此，这些研究高度适用于R21机制的目的。代谢型谷氨酸受体在调节神经元兴奋性、突触传递以及健康和疾病中的各种代谢功能中起着重要作用。鉴于这些受体中的许多主要是细胞内的，本申请试图确定细胞内代谢型谷氨酸受体的功能后果。针对细胞表面与细胞内受体的药物的未来研究可能会导致各种神经退行性疾病和神经精神疾病，如帕金森病，药物成瘾，焦虑和精神分裂症的新的治疗工具。

DESCRIPTION (provided by applicant): G-protein coupled receptors are well known for converting an extracellular signal into an intracellular response. Emerging data, however, suggest that some receptors are primarily localized on intracellular membranes where they may play a unique role in the cell's physiology. Recently we have shown that activation of mGlu5 metabotropic glutamate receptors expressed on striatal nuclear membranes leads to rapid, sustained nuclear calcium responses that can be blocked by receptor specific antagonists. Current results demonstrate that both sodium-dependent and independent transporters are involved in moving agonist across both plasma and nuclear membranes as inhibition of either transport system blocks agonist-induced nuclear calcium changes. Remarkably, non-transported agonists induce rapid, transient calcium responses in striatal neurons whereas transported ligands induce long, sustained calcium plateaus. Finally, ligand stimulation of nuclear receptors initiates at least one signaling cascade that is known to alter gene transcription and regulate many paradigms of synaptic plasticity. Because these findings represent a radical departure from traditional models emphasizing cell surface receptors and their ligands, they have important cellular ramifications both in terms of the concept, i.e. that nuclear receptors can regulate nuclear calcium, as well as for mGlu5-specific functions throughout development and in association with synaptic plasticity. The goal of the current application is to utilize our established striatal system together with our newly characterized pharmacological tools to determine the long term consequences of intracellular receptor activation. Using both a candidate gene and an unbiased genomic approach, we will test the primary hypothesis that activation of cell surface versus intracellular mGlu 5 receptors leads to differential changes in gene expression. Inasmuch as mGlu5 receptors are also involved in the pathophysiology of various neurodegenerative and neuropsychiatric disorders such as Parkinson's disease, drug addiction, anxiety and schizophrenia they represent attractive targets for drug discovery. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for these disorders. Thus these studies are highly applicable to the purpose of the R21 mechanism. The metabotropic glutamate receptors play fundamental roles in modulating neuronal excitability, synaptic transmission, and various metabolic functions in both health and disease. Given that many of these receptors are largely intracellular, this application seeks to determine the functional consequences of intracellular metabotropic glutamate receptors. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for various neurodegenerative and neuropsychiatric disorders such as Parkinson's disease, drug addiction, anxiety and schizophrenia.