MU OPIOID RECEPTOR--PHOSPHORYLATION AND DESENSITIZATION

描述：（申请人摘要） 拟议研究的总体目标是了解分子 阿片受体的作用机制，特别是阿片受体的作用机制 鸦片类药物成瘾的潜在原因 一个突出特点 吗啡类药物的最大优势是它们能够诱导耐受性和依赖性 在人类身上。 受体脱敏是细胞机制之一， 在这些神经适应过程中发挥着重要作用。 激动剂依赖性磷酸化有助于 多种G蛋白相关神经递质的脱敏 受体。 据推测，磷酸化在快速的 阿片受体介导的信号转导的衰减 鸦片类药物 受体磷酸化也有助于更长期的 脱敏事件，包括那些可能涉及耐受性和 依赖 为了验证这一假设，一项关于 克隆的μ阿片受体以及内源性μ阿片受体及其 提出了功能性后果。 这项研究的具体目标是： (1)为了表征小鼠神经元组织中μ受体的磷酸化， 大鼠脑，（2）确定受体的分子结构， 受体磷酸化所需的，和（3）检查mu的作用， 受体磷酸化在受体功能调节中的作用。 这项工作将提供有价值的信息分子和细胞 阿片受体的功能调节机制。 应当 影响了我们对药物分子作用机制的认识 耐受、依赖和成瘾。 这样的理解对于 镇痛和相加作用的药理学分离 鸦片类药物 对这些机制的理解将有望导致 合理治疗和预防药物滥用。

DESCRIPTION: (Applicant's Abstract) The overall goal of the proposed research is to understand the molecular mechanisms of opiate receptors' function, especially the mechanisms underlying the addictive effect of opiate drugs. A prominent characteristic of morphine-like drugs is their ability to induce tolerance and dependence in humans. Receptor desensitization is one of the cellular mechanisms that could play a significant role in these neuroadaptive processes. Agonist-dependent phosphorylation contributes to the mechanisms of desensitization in a wide variety of G-protein linked neurotransmitter receptors. It is hypothesized that phosphorylation plays a role in rapid attenuation of opiate receptor-mediated signal transduction in response to opiate drugs. Receptor phosphorylation also contributes to longer term desensitization events including those that may be involved in tolerance and dependence. To test this hypothesis, a study on the phosphorylation of cloned mu opiate receptor as well as endogenous mu opiate receptors and its functional consequences is proposed. The specific aims of this study are: (1) to characterize mu receptor phosphorylation in neuronal tissues of the rat brain, (2) to define the molecular structures of the receptor that are required for receptor phosphorylation, and (3) to examine the roles of mu receptor phosphorylation in functional regulation of the receptor. This work will provide valuable information of molecular and cellular mechanisms on the functional regulation of the opiate receptors. It should have an impact on our knowledge to the molecular mechanism of drug tolerance, dependence and addiction. Such understanding is fundamental to the pharmacological segregation of the analgesic and additive effects of opiate drugs. An understanding of these mechanisms will hopefully result in rational therapy for treatment and prevention of drug abuse.