Neuronal and glial AMPARs: auxiliary subunits as targets for ion channel regulation

我们大脑的功能依赖于无数细胞之间的化学通讯。这些化学物质中最重要的一种是谷氨酸盐，这是一种负责大部分快速兴奋信号的神经递质。谷氨酸通过与神经细胞之间接触点的受体蛋白结合而起作用，这种兴奋性信号传导的大多数关键特征是由一类特定谷氨酸受体的基本特性形成的-AMPA受体（AMPAR）。AMPAR无处不在;它们的活动是所有基本大脑功能的组成部分，包括感觉、思想、情感和记忆的过程。正因为如此，AMPAR的功能障碍会导致严重的神经系统疾病。特别地，允许钙离子进入细胞的AMPAR的一个亚类涉及几种病症的病因学，包括多发性硬化症、运动神经元疾病、癫痫、中风后或出生期间的脑损伤和脑肿瘤生长。由于AMPAR在正常认知中起着关键作用，它们也是旨在增强认知功能的药物治疗的靶点，特别是在神经退行性疾病如帕金森病和阿尔茨海默病中。如果我们要剖析它们在疾病发病机制中的作用，了解AMPAR至关重要。具体而言，迫切需要确定在细胞和分子水平上管理AMPAR功能的原则。最近，我们对这些过程的理解取得了显着进展，鉴定了与AMPAR直接相关并决定其性质和行为的蛋白质。两个蛋白质家族受到了特别的关注-跨膜AMPAR调节蛋白（TARP）和Cornichons（CNIH）。我们的研究旨在了解这些“辅助亚基”如何控制AMPA受体的功能，目的是确定治疗干预的潜在途径。我们将使用经证实的电生理学、成像和分子方法的组合来解决三个具体目标：（1）揭示不同的辅助蛋白如何影响内源性分子和外源性药物阻断或增强不同类型的AMPAR的方式;（2）鉴定对钙渗透性AMPAR调节重要的特异性辅助分子，和（3）阐明辅助蛋白在AMPAR变化中所起的作用，AMPAR变化被认为是涉及神经细胞和神经胶质的病理状况（炎性疼痛和白色物质损伤）的基础。这项研究的潜在应用和好处源于这样一个事实，即它将提供有关神经细胞和神经胶质中一类重要的谷氨酸受体调节的基本信息。它将巩固我们对正常大脑功能的理解，并强调治疗衰弱性疾病的策略。通过确定不同的辅助蛋白如何影响特定AMPAR亚型的药理学，它有可能为药物发现的新努力提供信息。

The functions of our brain rely on the chemical communication that takes place between its myriad cells. One of the most important of these chemicals is glutamate, a neurotransmitter responsible for a majority of fast excitatory signaling. Glutamate acts by binding to receptor proteins at points of contact between nerve cells, and most key features of this excitatory signaling are shaped by the basic properties of one specific class of glutamate receptor - the AMPA receptors (AMPARs). AMPARs are ubiquitous; their activity is integral to all fundamental brain functions, including the processes of sensation, thought, emotion and memory. Because of this, dysfunction of AMPARs causes serious neurological disorders. In particular, one subclass of AMPARs that allow the entry of calcium ions into cells is implicated in the aetiology of several conditions, including multiple sclerosis, motor neuron disease, epilepsy, brain damage following stroke or during birth, and brain tumor growth. As AMPARs play a key role in normal cognition, they are also targets for drug treatments aimed at enhancing cognitive function, notably in neurodegenerative conditions such as Parkinson's and Alzheimer's disease.Understanding AMPARs is essential if we are to dissect their role in disease pathogenesis. Specifically, there is an urgent need to determine the principles that govern AMPAR function at a cellular and molecular level. Recently, our understanding of these processes advanced significantly, with the identification of proteins that directly associate with AMPARs and dictate their properties and behaviour. Two families of proteins have received particular attention - the transmembrane AMPAR regulatory proteins (TARPs) and the cornichons (CNIHs). Our research is aimed at understanding how these 'auxiliary subunits' control the function of AMPA receptors, with the goal of identifying potential avenues for therapeutic intervention. We will use a combination of proven electrophysiology, imaging and molecular approaches to address three specific goals: (1) to reveal how different auxiliary proteins affect the way in which endogenous molecules and exogenous drugs block or potentiate different classes of AMPARs; (2) to identify the specific auxiliary molecules important for the regulation of calcium-permeable AMPARs, and (3) to elucidate the role played by auxiliary proteins in AMPAR changes thought to underlie pathological conditions involving nerve cells and glia (inflammatory pain and white matter damage). Potential applications and benefits of this research stem from the fact that it will provide fundamental information about the regulation of an important class of glutamate receptors in nerve cells and glia. It will consolidate our understanding of normal brain function and highlight strategies for treatment of debilitating conditions. By establishing how different auxiliary proteins affect the pharmacology of specific AMPAR subtypes it has the potential to inform new efforts in drug discovery.