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

基本信息

批准号：
8523032
负责人：
Luciann L. Cuenca
金额：
$ 2.95万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523032
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 Targeting 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 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 screening sensor structural biology therapeutic development tool vector voltage

项目摘要

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.

描述（由申请人提供）：疼痛是一种重要的感觉，用作生存机制，生物体通过疼痛意识到其环境中存在有害刺激。瞬时受体电位 Vanilloid-1 (TRPV1) 是一种多峰非选择性阳离子通道，已成为疼痛感知的关键角色。 TRPV1 会被有害热量 (>420C)、质子和辣椒素（辣椒中的“辣味”成分）等香草酸配体激活。与电压门控钾 (Kv) 通道类似，TRPV1 形成四聚体，每个原聚体由六个预测的跨膜片段 (S1-S6) 组成，具有较大的胞质 N 端和 C 端。 S1-S6 片段细分为 S1-S4 结构域（已知与香草醛相互作用）和 S5-P-loop-S6 孔结构域。近十年来，香草类化合物激活 TRPV1 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，该提案旨在阐明香草醛如何与 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，我提出了一种多管齐下的方法，从生化和结构生物学方法中收集信息。关于香草酸配体激活 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/或拮抗剂可能用作治疗与多种健康疾病相关的疼痛的疗法。