GABA(A) Receptor Modulation via the beta subunit

描述（由申请人提供）：GABAA受体传递CMS中的大部分突触抑制，通过该过程突触前中间神经元的兴奋阻止突触后主神经元的兴奋。GABAA受体也是苯二氮卓类和全身麻醉药的重要治疗靶点。受体功能也受到神经类固醇和许多滥用的催眠药物的调节。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学。该受体作为一种化学电压转换器，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换为超极化膜电位。当这些抑制信号的幅度、持续时间或时间被药物或疾病改变时，CMS的功能被深刻地改变。这项工作的基本假设是GABAA受体B亚基中的特定氨基酸定义了GABAA受体中的新型变构偶联途径。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。使用膜片钳电生理学，定点诱变，动力学和结构同源性建模的现代分子药理学工具，我们有新的位置在B亚基，是至关重要的变构激活的蛋白质之前，通道开放和调节通道活性的神经活性化学品。这些研究的结果将代表在了解药物对配体门控通道的作用方面向前迈进了一大步。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有助于精神分裂症，自闭症和癫痫等疾病的发病机制。最后，我们希望新的调节结合位点的特性将为我们提供一个新的治疗神经精神疾病的目标。

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.