SIGNAL TRANSDUCTION BY NEUROPEPTIDE RECEPTORS

我们研究的长期目标是了解信号的机制 通过神经肽受体转导。 K物质（神经激肽-A） 受体在正常和病理过程中都起重要作用， 包括记忆保留和类风湿性关节炎[1，2，3]。 的目标 本文提出的研究是确定结构-功能关系 使用神经激肽A受体作为模型系统， 神经肽受体，其具有七个疏水膜跨越 地区 配体结合后，神经肽受体与 G-蛋白来抑制它们的信号 结构-功能分析的一个关键突破是克隆了 受体的 人类神经激肽A受体已被我们克隆， 用于本分析。 具体目标是1）确定功能 K物质受体的结构域参与G蛋白相互作用， 产生神经激肽A受体和β 2- 肾上腺素能受体，利用不同的G蛋白。 优先于 肾上腺素能和毒蕈碱受体系统将指导选择 域要交换。2)确定翻译后的作用 神经激肽A受体的修饰。A.有潜力 神经激肽A受体上的肉豆蔻酰化和棕榈酰化位点。 的 将通过代谢标记分析这些位点的用途和重要性 实验和定点诱变。B）对神经激肽A的反应 很快就不敏感了。 在肾上腺素能系统中， 已经显示出由C-末端尾部的磷酸化控制。 的 神经激肽A受体C-末端尾部磷酸化的作用 将通过用32p体内标记和通过缺失诱变来分析 C-末端的尾巴。 一个简明的理解网站之间的互动重要 神经肽受体及其转导蛋白（G蛋白）是 了解信号转导机制所必需的 神经肽受体 G-蛋白相互作用的位点和 神经激肽A受体的翻译后修饰是 了解刺激或脱敏的机制， 对神经激肽A的反应，在正常调节的重要概念， 正常的受体功能 对信号机制的认识 通过这些受体的转导可能会产生更有效的治疗药物， 类风湿性关节炎等疾病，并用于分析记忆力 诱导B神经激肽A。

The long term goal of our research is to understand the mechanism of signal transduction by neuropeptide receptors. Substance-K (neurokinin-A) receptors play important roles in both normal and pathological processes, including memory retention and rheumatoid arthritis [l, 2, 3]. The goal of the research proposed here is to determine structure-function relationships of neuropeptide receptors using Neurokinin A receptor as a model system for neuropeptide receptors, which have seven hydrophobic membrane spanning regions. Following ligand binding, neuropeptide receptors couple with G-proteins to transduce their signals. A key breakthrough in analyzing structure-function is the cloning of the receptor. The human Neurokinin A receptor has been cloned by us and will be used in this analysis. Specific aims are 1) To determine functional domains of the substance-K receptor involved with G-protein interaction by producing chimeras between the neurokinin A receptor and the beta2- adrenergic receptor which utilize different G-proteins. Precedence from the adrenergic and muscarinic receptor systems will guide the choice of domains to be swapped. 2) To determine the role of post-translational modification of the Neurokinin A receptor. a) There are potential myristylation and palmitoylation sites on the Neurokinin A receptor. The use and importance of these sites will be analyzed by metabolic labelling experiments and site directed mutagenesis. b) The response to neurokinin A is rapidly desensitized. In the adrenergic system, desensitization has been shown to controlled by phosphorylation of the C-terminal tail. The role of phosphorylation of the C-terminal tail of the Neurokinin A receptor will be analyzed by in vivo labelling with 32p and by deletion mutagenesis of the C-terminal tail. A concise understanding of the sites important in the interaction between neuropeptide receptors and their transducing proteins (G-proteins) is necessary for understanding the mechanism of signal transduction by neuropeptide receptors. The site of G-protein interaction and the role of post-translational modifications of the Neurokinin A receptor are keys in understanding the mechanism of stimulation or desensitization of the response to Neurokinin A, important concepts in normal regulation of the proper receptor function. The understanding of mechanism of signal transduction by these receptors may lead to more potent drugs for treating diseases such as rheumatoid arthritis and for analysis of memory retention induced b Neurokinin A.