Alpha-Conotoxin - alpha9_alpha10 nAChRs

α-芋螺毒素 - alpha9_alpha10 nAChR

• 批准号: 8145706
• 负责人: J MICHAEL MCINTOSH
• 金额: $ 24.78万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145706
• 关键词: Acetylcholine; Advanced Development; Affinity; Alzheimer' s Disease; Amino Acid Substitution; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Proteins; Binding Sites; Biological Assay; Cells; Chimera organism; Cognition; Conotoxin; Data; Development; Disease; Drosophila acetylcholine receptor alpha-subunit; Drug or chemical Tissue Distribution; Electrophysiology (science); Elements; Environment; Epitopes; Face; Failure; Family; Fluorescent Probes; Funding; Gated Ion Channel; Grant; Image; Immune; Immune system; Individual; Inflammatory Response; Inhibitory Concentration 50; Investigation; Ion Channel; Ligand Binding; Ligands; Medicine; Modeling; Molecular; Molecular Probes; Molecular Structure; Muscle; Mutate; Mutation; Neuroglia; Neurons; Nicotinic Receptors; Pain; Paralysed; Parkinson Disease; Pathway interactions; Peptide Synthesis; Peptides; Perception; Peripheral; Pharmaceutical Preparations; Physiological Processes; Play; Population; Potassium Channel; Predisposition; Process; Progress Reports; Reporter; Resistance; Role; Schizophrenia; Sensory; Series; Site; Site-Directed Mutagenesis; Snake Venoms; Sodium Channel; Specificity; Structure-Activity Relationship; Testing; Tissues; Toxin; Translating; Venoms; Work; X-Ray Crystallography; Xenopus oocyte; alpha Bungarotoxin; alpha-Conotoxin; analog; base; chronic pain; disulfide bond; improved; member; motor control; nerve injury; new therapeutic target; novel; painful neuropathy; peptide analog; programs; receptor; three dimensional structure; two-dimensional; voltage

Nicotinic acetylcholine receptors (nAChRs) regulate critical physiological processes in the nervous and immune systems. These receptors represent potential therapeutic targets for new medicines to treat disorders of motor control (e.g., Parkinson's Disease), cognition (e.g., Alzheimer's Disease and schizophrenia), and sensory perception (e.g., chronic pain). Multiple subtypes of nAChRs exist, and different subtypes of these receptors underlie the pathophsyiology of various disease states. However, the ability to pharmacologically distinguish among these subtypes has been a problem. Conotoxins are unique peptides that not only are being used to overcome this problem but also serve as powerful probes for molecular characterization of nAChRs. We will utilize a newly discovered conotoxin RgIA, which specifically targets the alpha9alpha10 subtype of nAChR, to probe the molecular structure of the receptor. This subtype has a highly restricted tissue distribution and was recently shown to participate in a molecular pathway of neuropathic pain (i.e., pain induced by nerve injury). We will identify the features of RgIA that are responsible for its selectivity and high affinity for alpha9alpha10 nAChRs. We will use this information to create a battery of ligands, including fluorescent ones, to study alpha9alpha10 nAChRs in their native tissue environment. We have also exploited conotoxins to uncover and delineate previously unrecognized binding sites on the nAChR. In this regard, Project I will continue to work closely with discovery aspects of the Program to further characterize conotoxins that act at novel sites of nAChRs. Such investigation will enable further mechanistic understanding of the nAChR in particular and is expected to translate to improved understanding of ligandgated ion channels in general.

烟碱型乙酰胆碱受体（nAChR）调节神经和中枢神经系统中的关键生理过程， 免疫系统这些受体代表了新药治疗的潜在治疗靶点 运动控制障碍（例如，帕金森病）、认知（例如，阿尔茨海默病和精神分裂症）和感觉知觉（例如，慢性疼痛）。存在nAChR的多种亚型，并且这些受体的不同亚型是各种疾病状态的病理生理学的基础。然而，在这些亚型之间进行快速区分的能力一直是一个问题。芋螺毒素是一种独特的多肽，不仅可以用来克服这一问题，而且还可以作为分子生物学的强有力的探针。 nAChR的表征。我们将利用一种新发现的芋螺毒素RgIA，它专门针对nAChR的α 9 α 10亚型，探测受体的分子结构。该亚型具有高度限制的组织分布，并且最近显示参与神经性疼痛的分子途径（即，由神经损伤引起的疼痛）。我们将确定RgIA的特点，负责其选择性和高亲和力的α 9 α 10 nAChRs。我们将利用这些信息来创建一组配体，包括荧光配体，以研究天然组织中的α 9 α 10 nAChR 环境 我们还利用芋螺毒素来揭示和描绘以前未被识别的nAChR结合位点。在这方面，项目I将继续与该计划的发现方面密切合作，以进一步表征作用于nAChRs新位点的芋螺毒素。这样的研究将使进一步的机制，特别是了解nAChR，并有望转化为更好的理解配体化的 离子通道