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

瞬时受体电位 Vanilloid-1 通道的结构和功能

• 批准号: 8257621
• 负责人: Luciann L. Cuenca
• 金额: $ 3.37万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257621
• 关键词: Acute Pain; Address; Affinity; Affinity Chromatography; Agonist; Analgesics; Behavior; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Capsaicin; Cardiac; Cations; Cells; Chemicals; Chili Pepper; Chromatography; Coupled; Crystallography; DNA; Detergents; Development; Diazomethane; Disease; Drug Delivery Systems; Environment; Esthesia; Foundations; Goals; Health; Heating; Ion Channel; Knowledge; Length; Ligand Binding; Ligands; Location; Mass Spectrum Analysis; Mediating; Methods; Molecular; Molecular Conformation; Molecular Sieve Chromatography; Organism; Pain; Perception; Photoaffinity Labels; Pichia; Play; Potassium; Property; Proteins; Protocols documentation; Protomer; Protons; Recombinant Proteins; Research; Resolution; Role; Screening procedure; Sensory; Solid; Stimulus; Structure; System; Technology; Testing; Therapeutic; Vanilloid; analog; base; chronic pain; design; functional group; information gathering; insight; interest; large scale production; receptor; research study; respiratory; sensor; structural biology; therapeutic development; tool; vector; voltage

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.

描述（由申请人提供）：疼痛是一种非平凡的感觉，用作一种生存机制，通过这种机制，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（TRPV 1）是一种多模态非选择性阳离子通道，已成为疼痛感知的关键参与者。TRPV 1被有害热（> 420 ℃），质子和香草素配体如辣椒素（辣椒中的“辛辣”成分）激活。类似于电压门控钾（Kv）通道，TRPV 1形成四聚体，每个原聚体由六个预测的跨膜区段（S1-S6）组成，具有大的胞质N-和C-末端。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-环-S6孔结构域。在过去的十年中，类香草素对TRPV 1的激活一直是广泛研究的主题。然而，这些化合物激活TRPV 1的分子机制尚未完全了解。因此，该建议旨在阐明香草素如何与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耦合的分子细节。为了解决这些问题，我提出了一个多管齐下的方法，从生物化学和结构生物学方法收集信息。获得的关于通过香草素配体激活TRPV 1的知识将有助于开发TRPV 1激动剂和/或拮抗剂，其具有作为治疗与多种健康疾病相关的疼痛的治疗剂的潜在用途。 公共卫生相关性：该提案的长期目标是了解瞬时受体电位香草素-1（TRVP 1）离子通道被香草素配体激活的机制。具体来说，我感兴趣的是揭示参与配体结合的结构成分，以及配体结合如何被转换成通道门控。香草素配体对TRPV 1的激活具有生物医学意义，因为TRPV 1在疼痛感知中起重要作用，因为它充当有害化学和热刺激的传感器。详细了解TRPV 1被激活的分子基础将有助于设计/开发TRPV 1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。