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

描述(申请人提供)：疼痛是一种不平凡的感觉，作为一种生存机制，使生物体意识到其环境中存在有害刺激。瞬时受体电位香草酸-1(TRPV1)是一种多通道的非选择性阳离子通道，在痛觉中起关键作用。TRPV1被有毒的热(&gt；420C)、质子和香草素配体激活，如辣椒素，辣椒素是辣椒中的“辣”成分。与电压门控钾(Kv)通道类似，TRPV1形成四聚体，每个原型由六个预测的跨膜片段(S1-S6)组成，具有大的胞质N-端和C-端。S1-S6片段被细分为已知与香草素相互作用的S1-S4结构域和S5-P-loop-S6孔结构域。在过去的十年里，香草素对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(S)还不是很清楚。因此，这一提议试图阐明香草素如何与S1-S4结构域相互作用以及该区域的构象变化如何与通道门控相耦合的分子细节。为了解决这些问题，我提出了一种从生化和结构生物学方法中收集信息的多管齐下的方法。通过香草素配体激活TRPV1的知识将有助于开发TRPV1激动剂和/或拮抗剂，这些激动剂和/或拮抗剂具有潜在的用途，用于治疗与各种健康疾病相关的疼痛。 公共卫生相关性：这项建议的长期目标是了解香草素配体激活瞬时受体电位香草素1(TRVP1)离子通道的机制(S)。具体地说，我感兴趣的是揭示参与配体结合的结构成分，以及配体结合是如何转化为通道门控的。由于TRPV1作为有害化学和热刺激的感受器，在痛觉中起着重要的作用，因此，香草酸配体对TRPV1的激活具有重要的生物医学意义。详细了解激活TRPV1的分子基础将有助于设计/开发TRPV1激动剂和/或拮抗剂，用于治疗与呼吸系统(1)、消化系统(3)和心脏系统(4)的几种健康状况相关的急性和慢性疼痛。

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. PUBLIC HEALTH RELEVANCE: The long-term goal of this proposal is to understand the mechanism(s) by which the Transient Receptor Potential Vanilloid-1 (TRVP1) ion channel is activated by vanilloid ligands. Specifically, I am interested in uncovering the structural components participating in ligand binding and how ligand binding is transduced into channel gating. The activation of TRPV1 by vanilloid ligands is of biomedical interest since TRPV1 plays an important role in pain perception as it acts as a sensor of harmful chemical and thermal stimuli. A detailed understanding of the molecular basis by which TRPV1 is activated will be instrumental for the design/development of TRPV1 agonists and/or antagonists for the treatment of acute and chronic pain associated with several health conditions of the respiratory(1), digestive(3), and cardiac (4)systems.