GABA(A) Receptor Modulation via the beta subunit

描述（由申请人提供）：GABAA受体在CMS中传递大部分突触抑制，这是突触前中间神经元的兴奋阻止突触后主神经元兴奋的过程。GABAA受体也是苯二氮卓类药物和全身麻醉剂的重要治疗靶点。受体功能也被神经类固醇和许多被滥用的催眠药物所调节。GABAA受体基因的突变与家族性癫痫、精神分裂症和自闭症有关。然而，目前尚不清楚这些化学物质如何调节受体功能或这些突变如何在分子水平上导致受体功能障碍或疾病病理。受体作为一种化学到电压的传感器，在整个神经系统的各种神经元细胞类型中将抑制性化学信号转化为超极化膜电位。当这些抑制信号的振幅、持续时间或时间被药物或疾病改变时，CMS的功能就会发生深刻的改变。这项工作的基本假设是GABAA受体b亚基中的特定氨基酸在GABAA受体中定义了一种新的变构偶联途径。该项目的目标是i)表征受体上的新结合位点，ii)更好地理解支持快速抑制性神经传递的激活和调节的分子事件。利用膜片钳电生理学、位点定向诱变、动力学和结构同源建模等现代分子药理学工具，我们在b亚基中发现了新的位置，这些位置对于通道打开之前蛋白质的变构激活和神经活性化学物质对通道活性的调节至关重要。这些研究的结果将在理解药物作用于配体门控通道方面向前迈出一大步。此外，这些结果可能有助于理解GABAA受体基因的遗传突变如何促进精神分裂症、自闭症和癫痫等疾病的发病机制。最后，希望新的调节结合位点的表征将为我们治疗神经精神疾病提供新的靶点。

DESCRIPTION (provided by applicant): GABAA receptors convey the majority of synaptic inhibition in the CMS, the process by which excitation of a presynaptic interneuron prevents the excitation of a postsynaptic principal neuron. GABAA receptors also are important therapeutic targets for benzodiazepines and general anesthetics. Receptor function is also modulated by neurosteroids and many abused hypnotic drugs. Mutations in GABAA receptor genes have been linked to familial epilepsies, schizophrenia and autism. However, it is not known how these chemicals modulate receptor function or how these mutations contribute to receptor dysfunction or disease pathology at the molecular level. The receptor functions as a chemical to voltage transducer, converting inhibitory chemical signals into hyperpolarizing membrane potentials in a wide variety of neuronal cell types throughout the nervous system. When the amplitude, duration or timing of these inhibitory signals is altered either by drug or disease, the function of the CMS is profoundly altered. The underlying hypothesis of this work is that specific amino acids in the GABAA receptor b subunit define a novel allosteric coupling pathway in the GABAA receptor. The goals of this project are i) to characterize a new binding site on the receptor and ii) to better understand the molecular events that underpin the activation and modulation of fast inhibitory neurotransmission. Using the modern molecular pharmacologic tools of patch-clamp electrophysiology, site directed mutagenesis, kinetic and structure homology modeling, we have novel positions in the b subunit that are critical for the allosteric activation of the protein that precedes channel opening and for the modulation of channel activity by neuroactive chemicals. The results generated in these studies will represent a large step forward in understanding drug action on ligand-gated channels. Furthermore, these results may aid in understanding how inherited mutations in GABAA receptor genes contribute to the pathogenesis of diseases such as schizophrenia, autism and epilepsy. Finally, it is hoped that the characterization of the new modulatory binding site will provide us with a new target for treating neuropsychiatric diseases.