MULTIPLE ACTIVITY PATTERNS OF ACETYLCHOLINE RECEPTORS

这项研究的长期目标是了解分子基础。 神经系统中的突触传递，特别是 突触受体激活的机制是通过它们的 发射机。我们正在研究组织中表达的乙酰胆碱受体- 培养的细胞。我们的实验方法是使用重组DNA 技术以蛇点突变受体，表达突变体 在组织培养细胞中的受体，并使用单通道动力学 确定受体的功能如何被改变的方法 突变。第一个目标是了解通过什么机制 分子识别是在递质结合部位实现的。我们要 理解L)受体蛋白的机制 将传递分子与化学上相似的无机分子区分开来 离子，以及2)递质-受体相互作用的哪些方面 确定活化反应的速率和平衡。这个 第二个目标是研究构成分子事件的 受体连接的孔道的打开和关闭，即通道 门控。我们将研究受体的哪些部分决定了 通道打开和关闭的速率，以及4)分子 结合部位和孔道耦合的机理。第三个目标 是研究慢经络先天性肌无力的生物物理基础 综合征(SCCMS)，一种由基因自然突变引起的人类疾病 乙酰胆碱受体蛋白。5)我们将研究分子 这些突变使受体功能失调的机制。这个 拟议的研究将扩展我们对基本操作的知识 并将增加我们将能够 将这一知识应用于SCCMS和其他疾病的治疗 涉及烟碱型乙酰胆碱受体的胆碱能突触。

The long-term goal of this research is to understand the molecular basis of synaptic transmission in the nervous system, in particular the mechanisms by which synaptic receptors are activated by their transmitters. We are studying acetylcholine receptors expressed in tissue- cultured cells. Our experimental approach is use recombinant DNA technology to snake point mutations in the receptor, to express the mutant receptors in tissue-cultured cells, and to use single-channel kinetic methods to determine how the function of the receptors has been altered by the mutation. The first objective is to understand the mechanisms by which molecular recognition is achieved at the transmitter binding site. We want to understand l) the mechanisms by which the receptor protein distinguishes transmitter molecules from chemically-similar inorganic ions, and 2) which aspects of the transmitter-receptor interaction determine both the rates and equilibria of the activation reactions. The second objective is to investigate the molecular events that constitute the opening and closing of the receptor-linked pore, that is, channel gating. We will investigate 3) which parts of the receptor determine the rates at which the channel opens and closes, and 4) the molecular mechanisms by which the binding site and pore coupled. The third objective is to study the biophysical basis of slow channel congenital myasthenic syndrome (SCCMS), a human disease that arises from natural mutations in the acetylcholine receptor protein. 5) We will study the molecular mechanisms by which these mutations make the receptor dysfunctional. The proposed research will extend our knowledge of the fundamental operation of receptors, and will increase the likelihood that we will be able to apply this knowledge to the treatment of SCCMS and other diseases of cholinergic synapses that involve nicotinic acetylcholine receptors.