Neuroprotection by Novel Regulators of mGluR Signaling

谷氨酸激活介导快速突触传递的离子型谷氨酸受体（iGluR）， 调节细胞兴奋性的代谢型谷氨酸受体（mGluRs）。iGluRs在细胞外 钠和钙进入细胞，而I组mGluRs（1，5）导致钙从细胞中释放 细胞内储存。脑损伤如中风或局部缺血导致细胞外谷氨酸盐增加， iGluRs和mGluRs的不受控制的激活，以及细胞内钙的毒性积累， 细胞死亡的基本启动子。因此，用于治疗脑缺血的治疗策略已经集中在 iGluR和I组mGluR拮抗剂的使用。虽然iGluR拮抗剂在神经系统中具有神经保护作用， 模型缺血研究，可能是由于抑制细胞内钙积累，这些化合物 在临床试验中失败了。类似地，I组mGluR拮抗剂在模型缺血中具有神经保护作用。 研究，可能是由于细胞内钙积累的抑制，但大多数mGluR选择性 化合物进入大脑是很困难的。我们已经开始探索替代的神经保护策略， 使用蛋白质组学鉴定新的蛋白质或肽，其通过调节I组mGluR信号传导 在可接近的胞外氨基末端结构域的相互作用。我们的第一个蛋白质组 研究集中在第一组mGluR亚型，mGluRS，并揭示了一种新的相互作用， 克隆的细胞外蛋白，促进细胞存活，ADNP（活性依赖性神经保护蛋白）。 ADNP含有8个氨基酸的肽序列（NAPVSIPQ; NAP），其被证明是最小的 ADNP的活性成分，可诱导神经保护作用。临床前实验表明NAP具有强效作用 神经保护、记忆增强和神经营养特性。然而， NAP或ADNP的神经保护作用尚不清楚。我们的初步数据表明， NAP和ADNP的神经保护作用是调节I组mGluR信号传导。研究建议 本文的研究是重要的，因为1）它们开始描述NAP的神经保护机制， 外源肽和ADNP，一种内源性蛋白，2）它们提供了新的调节证据， mGluR信号通过肽或蛋白质相互作用在细胞外结构域，和3）他们提供了新的 脑缺血的治疗干预方法。

Glutamate activates ionotropic glutamate receptors (iGluRs) that mediate fast synaptic transmission, and metabotropic glutamate receptors (mGluRs) that modulate cell excitability. The iGluRs gate extracellular sodium and calcium entry into the cell, while the Group I mGluRs (1, 5) lead to the release of calcium from intracellular stores. Brain injury such as stroke or ischemia leads to increased extracellular glutamate, uncontrolled activation of iGluRs and mGluRs, and the toxic accumulation of intracellular calcium that is an essential initiator of cell death. Thus therapeutic strategies for the treatment of brain ischemia have focused on the use of iGluR and Group I mGluR antagonists. While iGluR antagonists are neuroprotective in modeled ischemia studies, likely due to inhibition of intracellular calcium accumulation, these compounds have failed in clinical trials. Similarly, Group I mGluR antagonists are neuroprotective in modeled ischemia studies, likely due to inhibition of intracellular calcium accumulation, yet delivery of most mGluR-selective compounds to the brain is difficult. We have begun to explore alternative neuroprotective strategies for brain ischemia using proteomics to identify novel proteins or peptides that modulate Group I mGluR signaling via interactions at the pharmacologically accessible extracellular amino terminal domain. Our first proteomic studies focused on the Group I mGluR subtype, mGluRS, and revealed a novel interaction with a recently cloned extracellular protein that promotes cell survival, ADNP (activity-dependent neuroprotective protein). ADNP contains an eight amino acid peptide sequence (NAPVSIPQ; NAP) that was shown to be the smallest active element of ADNP that can induce neuroprotection. Preclinical experiments show that NAP has potent neuroprotective, memory enhancing and neurotrophic properties. However, the mechanisms that underlie neuroprotection by NAP or ADNP are not known. Our preliminary data suggest that one mechanism of neuroprotection by NAP and ADNP is to regulate Group I mGluR signaling. The research studies proposed herein are important because 1) they begin to delineate the mechanisms of neuroprotection by NAP, an exogenous peptide, and ADNP, an endogenous protein, 2) they provide evidence for the novel regulation of mGluR signaling by peptide or protein interactions at the extracellular domain, and 3) they offer new approaches for therapeutic intervention in brain ischemia.