Functional Consequences of Nuclear mGlu5 Receptor Activation

描述(申请人提供)：G蛋白偶联受体是众所周知的将细胞外信号转化为细胞内反应的受体。然而，新出现的数据表明，一些受体主要定位在细胞内的膜上，在细胞的生理中可能发挥着独特的作用。最近我们发现，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，该反应可被受体特异性拮抗剂阻断。目前的结果表明，钠依赖和独立的转运体都参与了激动剂在质膜和核膜上的移动，因为抑制这两个转运体系统中的任何一个都会阻止激动剂诱导的核钙变化。值得注意的是，未转运的激动剂在纹状体神经元中诱导快速、瞬时的钙反应，而转运的配体诱导长期、持续的钙平台。最后，核受体的配体刺激启动了至少一个已知的改变基因转录和调节突触可塑性的信号级联反应。由于这些发现与强调细胞表面受体及其配体的传统模型截然不同，因此它们在核受体可以调节细胞核钙，以及mGlu5在整个发育过程中的特定功能以及与突触可塑性相关的概念方面都具有重要的细胞分支。目前应用的目标是利用我们已建立的纹状体系统和我们新鉴定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倚的基因组方法，我们将检验最初的假设，即细胞表面与细胞内mGlu 5受体的激活导致基因表达的差异变化。由于mGlu5受体还参与各种神经退行性疾病和神经精神疾病的病理生理学，如帕金森氏病、药物成瘾、焦虑和精神分裂症，它们是有吸引力的药物发现的靶点。未来针对细胞表面和细胞内受体的药物研究可能会为这些疾病带来新的治疗工具。因此，这些研究非常适用于R21机制的目的。在健康和疾病中，代谢型谷氨酸受体在调节神经元兴奋性、突触传递和各种代谢功能方面发挥着重要作用。鉴于许多这些受体主要是细胞内的，这一应用试图确定细胞内代谢性谷氨酸受体的功能后果。未来针对细胞表面药物和细胞内受体的研究可能会为各种神经退行性疾病和神经精神疾病带来新的治疗工具，如帕金森氏症、药物成瘾、焦虑和精神分裂症。

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.