Neuroprotection by Novel Regulators of mGluR Signaling

谷氨酸激活离子型谷氨酸受体(IGluRs)，介导快速突触传递，以及 调节细胞兴奋性的代谢性谷氨酸受体(MGluRs)。细胞外的iGluRs门 钠和钙进入细胞，而I组mGluRs(1，5)导致钙从 细胞内存储。中风或脑缺血等脑损伤会导致细胞外谷氨酸增加， IGluRs和mGluRs的不受控制的激活，以及细胞内钙的毒性积累是一种 细胞死亡的基本始作俑者。因此，治疗脑缺血的治疗策略成为关注的焦点。 关于iGluR和I组mGluR拮抗剂的使用。而iGluR拮抗剂具有神经保护作用 模拟的缺血研究，可能是由于抑制细胞内钙积累，这些化合物 在临床试验中都失败了。类似地，I组mGluR拮抗剂在模拟缺血中具有神经保护作用 研究，可能是由于抑制了细胞内钙的积累，但仍提供大多数mGluR选择性 化合物对大脑来说是困难的。我们已经开始探索大脑的替代神经保护策略 利用蛋白质组学确定通过调节I组mGluR信号的新蛋白质或多肽 药理上可及的胞外氨基末端区域的相互作用。我们的第一个蛋白质组 研究集中在组I mGluR亚型，mGluRs，并揭示了最近与一种新的相互作用 克隆的促进细胞存活的胞外蛋白，ADNP(活性依赖神经保护蛋白)。 ADNP包含一个八个氨基酸的肽序列(NAPVSIPQ；NAP)，它是被证明是最小的 ADNP的活性成分，可诱导神经保护。临床前实验表明NAP具有很强的药效 神经保护、增强记忆和神经营养特性。然而，其背后的机制 NAP或ADNP对神经的保护作用尚不清楚。我们的初步数据表明，一种机制 NAP和ADNP的神经保护作用是调节I组mGluR信号。研究报告建议 在这里很重要，因为1)它们开始描述NAP的神经保护机制，以及 外源肽和内源性蛋白ADNP，2)它们为新的调控提供了证据。 通过胞外区的多肽或蛋白质相互作用传递mGluR信号，以及3)它们提供了新的 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.