Alpha-Conotoxin - alpha9_alpha10 nAChRs

烟碱型乙酰胆碱受体(NAChRs)调节神经和 免疫系统。这些受体代表了治疗新药的潜在治疗靶点。 运动控制障碍(如帕金森氏病)、认知障碍(如阿尔茨海默病和精神分裂症)和感官知觉障碍(如慢性疼痛)。存在多种亚型的nAChRs，这些受体的不同亚型构成了不同疾病状态的病理生理基础。然而，在药理学上区分这些亚型的能力一直是个问题。芋螺毒素是一种独特的多肽，不仅被用来克服这个问题，而且还可以作为强大的分子探针。 NAChRs的特征。我们将利用一种新发现的芋螺毒素RgIA，它专门针对α9α10亚型的nAChR，来探索受体的分子结构。这个亚型的组织分布高度受限，最近被证明参与了神经病理性疼痛(即，神经损伤引起的疼痛)的分子通路。我们将确定RgIA对α9α10 nAChRs的选择性和高亲和力的功能。我们将利用这些信息来创造一组配体，包括荧光配体，来研究它们天然组织中的α9α10 nAChRs 环境。 我们还利用芋螺毒素发现并描绘了nAChR上以前未被识别的结合位点。在这方面，项目I将继续与该计划的发现方面密切合作，以进一步确定在nAChRs的新位置起作用的芋螺毒素的特征。这样的研究将使对nAChR特别是nAChR的进一步机械性理解成为可能，并有望转化为对配体门控的更好理解 一般的离子通道。

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.