Mechanism of Allosteric Modulator Action at the Ionotropic Glutamate Receptor

描述（由申请人提供）：离子型谷氨酸受体（iGluR）是配体门控离子通道，其形成跨膜阳离子渗透通道，在激动剂结合时打开。iGluR是中枢神经系统（CNS）中兴奋性突触传递的主要介质。iGluRs（AMPAR）的（S）-2-氨基-3-（3-羟基-5-甲基-4-异恶唑）丙酸（AMPA）亚型对于CNS中的快速兴奋性神经传递以及可能是学习和记忆基础的长时程增强（LTP）的表达和维持是必需的。AMPAR的功能障碍涉及几种神经退行性疾病，如阿尔茨海默病和肌萎缩性侧索硬化症（ALS）、认知缺陷、癫痫、精神分裂症和情绪障碍。因此，了解AMPAR的结构和功能关系可能会导致有价值的治疗药物的开发。我们认为AMPAR的胞外氨基末端结构域（ATD）可能是以变构方式调节AMPAR通道活性的潜在非竞争性激动剂/拮抗剂的靶标。与直接靶向神经递质结合位点并破坏受体在突触传递中的正常功能的竞争性药物相比，从治疗角度来看，这些非竞争性化合物更理想。我们建议采取基于结构的药物发现方法，重点是AMPAR-ATD。具体目标是：（1）确定AMPAR-ATD的高分辨率晶体结构，并通过基于结构的诱变和电生理学表征AMPAR-ATD的功能;（2）鉴定和表征ATD靶向的AMPAR变构调节剂。拟议的研究将进一步加深我们对控制AMPAR通道活性的调控机制的理解，并确定靶向AMPAR-ATD的潜在候选药物，使我们能够微调AMPAR的活性。这些非竞争性化合物将为治疗用途提供令人兴奋的前景。公共卫生相关性：AMPA亚型谷氨酸受体（AMPAR）的功能障碍与神经退行性疾病如阿尔茨海默病和肌萎缩侧索硬化（ALS）、认知缺陷、癫痫、精神分裂症和情绪障碍有关。本研究旨在研究AMPARs胞外氨基末端结构域（ATD）的结构与功能关系。我们认为，AMPAR ATD可能是一个潜在的非竞争性调节剂的新目标。这些化合物以变构方式调节AMPAR通道活性，有望成为新一代治疗剂。

DESCRIPTION (provided by applicant): Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that form transmembrane, cation- permeable channels which open upon agonist binding. iGluRs are the major mediators of excitatory synaptic transmission in the central nervous system (CNS). The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) subtype of iGluRs (AMPAR) is essential for the fast excitatory neurotransmission in the CNS and expression and maintenance of long-term potentiation (LTP) that may underlie learning and memory. Malfunction of AMPAR has been implicated in several neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS), cognitive deficits, epilepsy, schizophrenia, and mood disorders. Therefore, an understanding of the structure and function relationships in AMPARs may lead to the development of valuable therapeutic agents. We believe that the extracellular amino-terminal domain (ATD) of AMPARs may be a target for potential non- competitive agonists/antagonists which modulate AMPAR channel activity in an allosteric manner. In comparison to the competitive drugs that directly target the neurotransmitter-binding site and disrupt the receptor's normal function in synaptic transmission, these non-competitive compounds are more desirable from a therapeutic perspective. We propose to take a structure-based drug discovery approach focusing on the AMPAR-ATD. The specific aims are: (1) Determine the high-resolution crystal structure of the AMPAR-ATD, and characterize the function of the AMPAR-ATD by structure-based mutagenesis and electrophysiology; (2) Identify and characterize the ATD-targeting allosteric modulators for AMPAR. The proposed studies will further our understanding of the regulatory mechanisms controlling channel activity of AMPARs, and identify potential drug candidates that target the AMPAR-ATD and allow us to fine-tune the activities of AMPAR. These non-competitive compounds will provide exciting promise for therapeutic use. PUBLIC HEALTH RELEVANCE: Malfunction of the AMPA subtype glutamate receptors (AMPARs) has been implicated in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS), cognitive deficits, epilepsy, schizophrenia, and mood disorders. We propose to study the structure and function relationships in the extracellular amino-terminal domain (ATD) of AMPARs. We believe that the AMPAR-ATD may be a novel target for potential non-competitive modulators. These compounds modulate AMPAR channel activity in an allosteric manner and hold promise to be a new generation of therapeutic agents.