Structure and Function of the Transient Receptor Potential Vanilloid-1 Channel

描述（由申请人提供）：疼痛是一种重要的感觉，作为一种生存机制，生物体通过它意识到环境中有害刺激的存在。瞬时受体电位香草素-1 （TRPV1）是一种多模态非选择性阳离子通道，在疼痛感知中起着关键作用。TRPV1会被有毒的热量（bb0 - 420C）、质子和香草配体（如辣椒素）激活，辣椒素是辣椒中的“辛辣”成分。与电压门控钾（Kv）通道类似，TRPV1形成四聚体，每个原聚体由6个预测的跨膜片段（S1-S6）组成，具有大的细胞质N和c端。S1-S6段被细分为S1-S4结构域（已知与香草类相互作用）和S5-P-loop-S6孔隙结构域。在过去的十年中，香草类物质对TRPV1的激活一直是广泛研究的主题。然而，这些化合物激活TRPV1的分子机制尚不清楚。因此，本研究旨在阐明香草蛋白如何与S1-S4结构域相互作用的分子细节，以及该区域的构象变化如何与通道门控相耦合。为了解决这些问题，我提出了从生物化学和结构生物学方法收集信息的多管齐下的方法。获得关于香草素配体激活TRPV1的知识将有助于TRPV1激动剂和/或拮抗剂的开发，这些药物可能用于治疗与各种健康疾病相关的疼痛。

DESCRIPTION (provided by applicant): Pain is a non trivial sensation used as a survival mechanism by which organisms are made aware of the presence of harmful stimuli in their environment. Transient Receptor Potential Vanilloid-1 (TRPV1), a polymodal non-selective cation channel, has emerged as a key player in pain perception. TRPV1 is activated by noxious heat (>420C), protons, and vanilloid ligands such as capsaicin, the "spicy hot" component in chili peppers. Similar to voltage-gated potassium (Kv) channels, TRPV1 forms tetramers with each protomer consisting of six predicted transmembrane segments (S1-S6) with large cytosolic N- and C-termini. The S1-S6 segments are subdivided into the S1-S4 domain, known to interact with vanilloids, and the S5-P-loop-S6 pore domain. TRPV1 activation by vanilloids has been the subject of extensive research in the last decade. Nevertheless, the molecular mechanism(s) by which these compounds activate TRPV1 is not well understood. Hence, this proposal seeks to elucidate the molecular details as to how vanilloids interact with the S1-S4 domain and how conformational changes in this region are coupled to channel gating. To address these questions, I propose a multi-pronged approach gathering information from both biochemical and structural biology methods. Knowledge gained about TRPV1 activation by vanilloid-ligands will be useful for the development of TRPV1 agonists and/or antagonists with potential uses as therapeutics for the treatment of pain associated with a variety of health diseases.