Structural studies of CaV alpha2delta subunits and interaction with anti-nocicept

描述(申请人提供)：电压门控钙通道CaVa2d亚基是两种加巴喷丁类药物的作用部位，加巴喷丁(Neurontin)和普瑞巴林(Lyrica)，用于治疗神经性疼痛、纤维肌痛、偏头痛、癫痫和一些情绪障碍。尽管CaVa2d与神经系统疾病的治疗有直接联系，但对CaVa2d的高分辨率分子结构、CaVa2d影响电压门控钙通道功能的详细分子机制、加巴喷丁和普瑞巴林如何与CaVa2d结合并调节电压门控钙通道活性的研究尚不清楚。我们试图确定CaVa2d和CaVa2d与加巴喷丁类药物的络合物的高分辨结构。我们致力于开发合适的表达系统来生产用于结晶学研究的CaVa2d蛋白，并解决CaVa2d的高分辨结构。这项工作将揭示CaVa2d功能的基本结构，并揭示加巴喷丁类药物如何与CaVa2d相互作用。这一知识将直接关系到了解加巴喷丁类药物的基本作用机制，并应有助于开发更好的疗法，改善疼痛和广泛的神经系统和情绪障碍的治疗。 公共卫生相关性：电压门控钙通道是用于治疗疼痛、癫痫、偏头痛、纤维肌痛和情绪障碍的药物的靶标。我们的工作旨在确定这些药物如何与通道功能相互作用并影响通道功能的分子结构。这些知识对于改进目前的治疗方法和开发更有效的治疗各种神经系统疾病的方法是不可或缺的。

DESCRIPTION (provided by applicant): The voltage-gated calcium channel CaVa2d subunit is the site of action of two gabapentinoid drugs, gabapentin (Neurontin) and pregabalin (Lyrica), that are used to treat neuropathic pain, pain associated with fibromyaglia, migraine, epilepsy, and a number of mood disorders. Despite the direct connection between CaVa2d and the treatment of nervous system disorders, nothing is known about CaVa2d molecular structure at high resolution, the detailed molecular mechanisms by which CaVa2d affects voltage-gated calcium channel function, or how gabapentin and pregabalin bind to CaVa2d and modulate voltage-gated calcium channel activity. We seek to determine the high-resolution structure of CaVa2d and CaVa2d complexes with gabapentinoid drugs. Our efforts are directed at developing the appropriate expression systems to produce CaVa2d proteins for crystallographic study and to solve the high-resolution structure of CaVa2d. This work should unveil the fundamental structures that underlie CaVa2d function and reveal how gabapentinoid drugs interact with CaVa2d. This knowledge will bear directly on understanding the basic mechanisms of action of gabapentinoid drugs and should facilitate the development of better therapeutics that will improve the treatment of pain and a wide range of nervous system and mood disorders. PUBLIC HEALTH RELEVANCE: Voltage-gated calcium channels are the targets of drugs that are used to treat pain, epilepsy, migraine, fibromyalgia, and mood disorders. Our work aims to determine the molecular architecture that underlies how such drugs interact with and affect channel function. Such knowledge is indispensable for the improvement of current therapies and development of more efficacious treatments for a variety of nervous system disorders.