Structural basis of TRPC channel function and regulation

TRPC通道功能与调节的结构基础

• 批准号: 7567562
• 负责人: Jian Yang
• 金额: $ 35.22万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7567562
• 关键词: 1,2-diacylglycerol; Affinity; Agonist; Amino Acid Sequence; Amino Acid Sequence Homology; Amino Acids; Asthma; Binding; Binding Sites; Biological Process; Blood; Blood Vessels; Brain; C-terminal; Calcium; Calmodulin; Cardiovascular Diseases; Cardiovascular Physiology; Cell membrane; Cell surface; Cells; Cellular Structures; Chronic Obstructive Airway Disease; Complex; Development; Diglycerides; Exhibits; Family; Feedback; Focal Segmental Glomerulosclerosis; G-Protein-Coupled Receptors; Genes; Growth Cones; Heart; Human; Hydrolysis; Hypertension; Inherited; Ion Channel; Kidney; Kidney Diseases; Kidney Failure; Kinetics; Link; Literature; Lung; Mediating; Molecular; Morphology; Muscle Tonus; Mutation; N-terminal; Names; Nerve Growth Factor Receptors; Pathway interactions; Pattern; Pheromone; Phosphatidylinositol 4,5-Diphosphate; Phospholipase C; Play; Property; Protein Isoforms; Proteins; Pseudogenes; Regulation; Reporting; Research; Resolution; Role; Sequence Alignment; Sex Behavior; Signaling Molecule; Signaling Protein; Site; Smooth Muscle; Structure; Surface Properties; Testing; Vesicle; Work; axon guidance; base; density; desensitization; falls; forging; human disease; interest; kidney cell; member; mutant; neurite growth; neuronal excitability; neurotransmitter release; novel therapeutics; prevent; public health relevance; receptor; receptor coupling; relating to nervous system; respiratory smooth muscle; scaffold; treatment strategy

DESCRIPTION (provided by applicant): The long-term objective of this research is to understand the molecular and structural mechanisms of the function of transient receptor potential (TRP) channels. In particular, we will focus on the canonical TRP (TRPC) channels, which are present in blood vessels, heart, lung, kidney and brain and are involved in regulating diverse biological processes ranging from neural and cardiovascular functions to sexual behavior. The seven members of the TRPC channel family conduct calcium into cells and are in turn regulated by intracellular calcium. All TRPC proteins interact directly with calmodulin (CaM), a ubiquitous calcium sensing protein, which may mediate calcium-dependent feedback regulation of TRPC channel activity and function. Our specific aims are to solve the high-resolution crystal structure of the complex of CaM and each of the four putative CaM-binding sites in TRPC proteins and to study the molecular mechanism and functional impact of CaM binding to each site. Our central hypothesis is that CaM forms distinct interactions with each TRPC site and these interactions regulate channel properties and functions in a channel-specific fashion. Mutations in TRPC channels have been linked to focal and segmental glomerulosclerosis, a hereditary kidney disorder leading to renal failure, and the abundance of TRPC channels in airway smooth muscles and blood vesicles suggest that their malfunction could play a role in asthma, chronic obstructive pulmonary disease, hypertension and various types of cardiovascular diseases. Thus, our studies will not only provide a better understanding of the function and regulation of these biologically important ion channels but also facilitate the development of new therapeutic strategies for the treatment of a host of human diseases. PUBLIC HEALTH RELEVANCE: TRPC channels are found in blood vessels, heart, lung, kidney and brain and are involved in regulating numerous biological processes ranging from neural and cardiovascular functions to sexual behavior. Malfunction of these channels may cause human diseases such as asthma and various types of cardiovascular diseases. A better understanding of how these channels work may provide new ways to treat a host of human diseases.

描述（由申请人提供）：这项研究的长期目标是了解瞬态受体电位（TRP）通道功能的分子和结构机制。特别是，我们将重点关注血管，心脏，肺，肾脏和大脑中存在的规范TRP（TRPC）通道，并参与调节从神经和心血管功能到性行为的多种生物学过程。 TRPC通道家族的七个成员将钙传导到细胞中，然后受细胞内钙调节。所有TRPC蛋白都与钙调蛋白（CAM）直接相互作用，钙调蛋白（CAM）是一种无处不在的钙传感蛋白，该蛋白可能介导TRPC通道活性和功能的钙依赖性反馈调节。我们的具体目的是解决CAM复合物的高分辨率晶体结构，以及TRPC蛋白中四个推定的CAM结合位点中的每个晶体结构，并研究CAM与每个位点结合的分子机制和功能影响。我们的中心假设是CAM与每个TRPC站点形成不同的相互作用，这些相互作用以通道特定的方式调节信道特性和功能。 Mutations in TRPC channels have been linked to focal and segmental glomerulosclerosis, a hereditary kidney disorder leading to renal failure, and the abundance of TRPC channels in airway smooth muscles and blood vesicles suggest that their malfunction could play a role in asthma, chronic obstructive pulmonary disease, hypertension and various types of cardiovascular diseases.因此，我们的研究不仅将更好地理解这些生物学上重要的离子通道的功能和调节，而且还促进了治疗许多人类疾病的新治疗策略的发展。公共卫生相关性：在血管，心脏，肺，肾脏和大脑中发现TRPC通道，并参与调节从神经和心血管功能到性行为的许多生物学过程。这些通道的故障可能导致人类疾病，例如哮喘和各种类型的心血管疾病。更好地了解这些渠道的工作方式可能会提供治疗许多人类疾病的新方法。