Neurosteroid Modulation of GABA(A) Receptors

GABA(A) 受体的神经类固醇调节

• 批准号: 6688947
• 负责人: Bruce A Bamber
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6688947
• 关键词: Neurosteroid; Modulation; GABA; Receptors

DESCRIPTION (provided by applicant): Epilepsy is a debilitating disease that affects 1-2% of the population. Anticonvulsant drug therapy is the treatment of choice, however about 30% of epilepsies are intractable to drug therapy, and necessitate surgical removal of brain tissue. In addition, anticonvulsant drugs reduce neuronal excitability non-specifically throughout the brain, leading to sedation and somnolence as side effects. Thus, there is an ongoing need to develop new anti-epileptic drugs. The overall goals of the proposed research are to help develop new anti-epileptic drug therapies by investigating the mechanisms of a new class of anticonvulsant drugs, the neurosteroids. Neurosteroids are synthesized in the brain, and regulate neuronal excitability by modulating GABAA receptors (the major inhibitory neurotransmitter receptors in the brain). Synthetic neurosteroids have proven to be effective anti-epileptic drugs in clinical trials, even against otherwise drug resistant epilepsies. Moreover, neurosteroids can potentially be engineered for greater specificity, to reduce side-effects. Two approaches will be taken to better understand neurosteroid modulation of GABAA receptors. First, to gain fundamental insights into neurosteroid mechanisms, a simple, well-characterized steroid-receptor interaction will be studied: The inhibition of the C. elegans UNC-49 receptor by pregnenolone sulfate (PS). Rapid ligand exchange methods will be used to characterize the mechanism of PS modulation of UNC-49, and to determine how the key residues act as effectors of PS modulation. Results of this study will be applicable to understanding neurosteroid modulation in humans because UNC-49 is a highly conserved GABAA receptor homologue. Second, the unique pharmacological properties of UNC-49 will be exploited in domain swap experiments to directly identify residues important for neurosteroid modulation in human GABAA receptors. The results of both approaches will increase understanding of how endogenous neurosteroids regulate seizure susceptibility, and will aid the design of new anti-epileptic drugs.

描述（由申请人提供）：癫痫是一种使人衰弱的疾病，影响 1-2% 的人口。抗惊厥药物治疗是首选治疗方法，但约 30% 的癫痫难以药物治疗，需要手术切除脑组织。此外，抗惊厥药物非特异性地降低整个大脑的神经元兴奋性，导致镇静和嗜睡等副作用。因此，持续需要开发新的抗癫痫药物。拟议研究的总体目标是通过研究新型抗惊厥药物神经类固醇的机制来帮助开发新的抗癫痫药物疗法。神经类固醇在大脑中合成，并通过调节 GABAA 受体（大脑中主要的抑制性神经递质受体）来调节神经元兴奋性。 在临床试验中，合成神经类固醇已被证明是有效的抗癫痫药物，甚至可以对抗其他耐药性癫痫。此外，神经类固醇可以被设计为具有更高的特异性，以减少副作用。将采取两种方法来更好地了解 GABAA 受体的神经类固醇调节。首先，为了获得对神经类固醇机制的基本了解，将研究一种简单、特征明确的类固醇-受体相互作用：孕烯醇酮硫酸盐 (PS) 对线虫 UNC-49 受体的抑制。快速配体交换方法将用于表征 UNC-49 的 PS 调节机制，并确定关键残基如何充当 PS 调节的效应子。这项研究的结果将适用于了解人类神经类固醇的调节，因为 UNC-49 是一种高度保守的 GABAA 受体同源物。其次，UNC-49独特的药理学特性将在结构域交换实验中被利用，以直接识别对人类GABAA受体中神经类固醇调节重要的残基。这两种方法的结果将增加对内源性神经类固醇如何调节癫痫易感性的理解，并将有助于新型抗癫痫药物的设计。