Structure and Function of the Acetylcholine Receptor

描述(申请人提供)：我们的长期目标是了解快速激活的突触受体如何将化学信号转换为电信号，以及疾病和治疗药物如何改变这一过程。化学-电转导过程是神经系统正常运作的基础，但其机制和结构基础却鲜为人知。为了了解化学-电转导，拟议的研究将确定神经递质乙酰胆碱(ACh)如何激活来自随意骨骼肌的ACh受体(AChRs)和来自炎症系统神经元和细胞的AChRs。特别是，我们将通过结合高分辨率单通道记录、动力学分析和结构扰动来解决在理解激活机制方面的主要空白。首先，我们将定义作为AChR激活基础的基本反应步骤，然后确定参与每个反应步骤的结构。其次，我们将描述激动剂疗效的结构和机制基础。第三，我们将定义AChR激活中协同性的结构基础。这个项目的完成将产生 对化学-电转导的机理和结构的了解适用于治疗药物的设计和神经疾病的治疗，包括肌肉无力障碍、帕金森和阿尔茨海默氏症以及精神分裂症。

DESCRIPTION (provided by applicant): Our long-term goal is to understand how rapidly-activated synaptic receptors convert a chemical signal into an electrical one, and how disease and therapeutic drugs alter this process. The process of chemo-electrical transduction is fundamental to the proper functioning of the nervous system, yet its mechanistic and structural bases are poorly understood. Toward understanding chemo-electrical transduction, the proposed studies will determine how the neurotransmitter acetylcholine (ACh) activates ACh receptors (AChRs) from voluntary skeletal muscle and alpha7 AChRs from neurons and cells of the inflammatory system. In particular, we will address major gaps in understanding the activation mechanism through a combination of high resolution single channel recording, kinetic analyses and structural perturbations. First, we will define elementary reaction steps that underlie AChR activation, and then identify structures that mediate each reaction step. Second, we will delineate structural and mechanistic bases of agonist efficacy. Third, we will define structural underpinnings of cooperativity in AChR activation. Completion of this project will yield both mechanistic and structural understanding of chemo-electrical transduction applicable to therapeutic drug design and treatment of neurological diseases including muscle weakness disorders, Parkinson's and Alzheimer's diseases and schizophrenia.