Mechanisms of Neurotransmitter-Gated Ion Channels

五聚体配基门控离子通道超家族是突触的四个超家族之一 动物体内存在的离子亲和性受体；另外三种是兴奋性谷氨酸受体，即ATP门控受体 阳离子通道(P2X)和酸敏离子通道(ASIC)。突触后pLGICs介导快速突触 突触前pLGIC调节其他神经递质的释放。此外，还有更多 最近，一些pLGIC被认为是参与非神经元现象的最多的 令人信服的证据表明，α7烟碱型乙酰胆碱受体在炎症中发挥了作用。重要的是 PLGICs是治疗药物(如苯二氮类药物和麻醉剂)和娱乐药物的靶标。 (如尼古丁)，它们的功能障碍通常与神经系统疾病有关--包括神经病理性疾病 糖尿病、先天性癫痫、精神分裂症和阿尔茨海默病患者的疼痛。我们知道的很多 这些离子通道的结构和功能。然而，合理药物设计的进展--毫无疑问， 对我们基本知识的最有趣和潜在回报的应用--在一定程度上远远落后于 因为我们对结构如何在pLGIC中产生功能的理解仍然不完整。在这里，我们 提出实验工作(电生理学、放射性配基结合分析和直接结构方法) 和计算工作(分子和布朗动力学模拟，以及静电计算) 将使我们能够：1)理解配体结合和门控之间的“耦合”。我们将挑战 普遍认为胞外区和跨膜区在功能上是自主的 为使通道作为一个整体发挥作用，需要将这些部件连接在一起；2)确定这些部件的结构 并阐明膜对其构象的影响 自由能景观；以及3)表征选择性过滤器上的侧链构象对 阳离子对阴离子的选择性。总的来说，这三个目标涵盖以下三个最基本的方面 配体门控离子通道，即配体结合、门控/脱敏和离子传导/电荷 选择性。

The superfamily of pentameric ligand-gated ion channels (pLGICs) is one of the four superfamilies of synaptic ionotropic receptors present in animals; the other three are the excitatory glutamate receptors, the ATP-gated cation channels (P2X), and the acid-sensing ion channels (ASIC). Postsynaptic pLGICs mediate fast synaptic transmission, whereas presynaptic pLGICs modulate the release of other neurotransmitters. In addition, more recently, some pLGICs have been proposed to be involved in non-neuronal phenomena with the most compelling evidence suggesting a role for the α7 nicotinic acetylcholine receptor in inflammation. Importantly, pLGICs are the target of therapeutic drugs (such as benzodiazepines and anesthetics) and recreational drugs (such as nicotine), and their malfunction is often associated with neurological disease—including neuropathic pain in diabetic patients, congenital epilepsy, schizophrenia and Alzheimer's disease. Much is known about the structure and function of these ion channels. However, progress in rational drug design—undoubtedly, a most intriguing and potentially rewarding application of our basic knowledge—has lagged far behind in part because our understanding of how structure gives rise to function in pLGICs remains incomplete. Here, we propose experimental work (electrophysiology, radioligand-binding assays, and direct structural approaches) and computational work (molecular and Brownian dynamics simulations, and electrostatic calculations) that will allow us to: 1) Understand the “coupling” between ligand-binding and gating. We will challenge the prevailing view that the extracellular domain and the transmembrane domain form functionally autonomous units that need to be “coupled” for the channel to function as a whole; 2) Determine the structure of these channels in functionally well-defined states and elucidate the effect of the membrane on their conformational free-energy landscapes; and 3) Characterize the impact of side-chain conformation at the selectivity filter on cation-versus-anion selectivity. Collectively, these three aims cover the three most fundamental aspects of ligand-gated ion channels, namely, ligand binding, gating/desensitization, and ion conduction/charge selectivity.