Opioid Binding to U51: A Human herpes Virus Protein

描述：(申请人提供) 人类疱疹病毒(HHV)-6和HHV-7是感染人类的病毒 中枢神经系统和T淋巴细胞。与人类免疫缺陷病毒密切相关的HHV-6 HHV-7在基因水平上经常与疾病有关，特别是 在免疫功能受损的人和艾滋病患者中。HHV-6和HHV-7 表达一种7-跨膜G蛋白偶联受体U51，该受体已被 被鉴定为阿片受体同系物，共有50%以上 与Kappa阿片受体的序列相似性。HHV-6和-7 U51股票 与Kappa、Mu和Delta阿片受体的序列相似性高于 与任何其他克隆的蛋白质结合。HHV-6 U51是一种趋化因子受体，它与 趋化因子RANTES和其他β趋化因子，如嗜酸性粒细胞趋化因子、单核细胞 趋化蛋白1、3和4。而HHV-7 U51可能与β结合 趋化因子，这一点还没有得到明确的证实，将在 拟议的研究，将审查阿片类药物与两者的相互作用 HHV-6 U51和HHV-7 U51。需要检验的总体假设是，U51 与趋化因子结合的蛋白质，是人类Kappa阿片类药物的同系物 受体，将结合一些阿片类药物，这些阿片类药物将激活U51 受体，调节RANTES的结合和功能。以下是 将测试特定的目标：1)确定阿片类药物是否会抑制结合 趋化因子[125I]RANTES对HHV-6和HHV-7 U51蛋白的作用；2)测定 如果阿片类药物激活了U51蛋白，用[35S]GTP GammaS测量 结合实验；以及3)确定阿片类药物是否调节RANTES诱导 刺激[35S]GTP-GammaS结合。这项提议有资格被砍掉 EDGE基础研究奖，因为如果阿片类药物与趋化因子受体结合 U51，这一发现将显示两种β趋化因子的共同受体。 和阿片类药物。此外，由于HHV-6和HHV-7感染T淋巴细胞和 人类中枢神经系统的细胞，这可能导致表达 一种仅存在于人类神经元和T细胞中的新型阿片受体 淋巴细胞。

DESCRIPTION: (provided by the applicant) The human herpes virus (HHV)-6 and HHV-7 are viruses that infect the human central nervous system and T lymphocytes. HHV-6, which is closely related to HHV-7 at the genetic level, is frequently associated with disease, particularly in immunocompromised persons and persons with AIDS. Both HHV-6 and HHV-7 express a 7-transmembrane G-protein coupled receptor, U51, which has been identified as an opioid receptor homologue, sharing greater than 50 percent sequence similarity with the Kappa opioid receptor. HHV-6 and -7 U51 share greater sequence similarity with the Kappa, mu and delta opioid receptors than with any other cloned protein. HHV-6 U51 is a chemokine receptor, which binds the chemokine RANTES, and other beta chemokines, such as eotaxin, monocyte chemoattractant protein 1, 3, and 4. While HHV-7 U51 probably binds beta chemokines, this has not been definitely proven and will be addressed in the proposed studies, which will examine the interactions of opioids with both HHV-6 U51 and HHV-7 U51. The overall hypothesis to be tested is that the U51 protein, which binds chemokines and is a homologue of the human Kappa opioid receptor, will bind some opioids, and that these opioids will activate the U51 receptor and regulate the binding and function of RANTES. The following specific aims will be tested: 1) Determine if opioids will inhibit the binding of the chemokine [125I]RANTES to the HHV-6 and HHV-7 U51 protein; 2) Determine if opioids activate the U51 protein, as measured with the [35S]GTPgammaS binding assay; and 3) Determining if opioids modulate RANTES-induced stimulation of [35S]GTPgammaS binding. This proposal qualifies for a Cutting Edge Basic Research Award because if opioids bind to the chemokine receptor U51, this finding would demonstrate a common receptor for both beta chemokines and opioids. In addition, because HHV-6 and -7 infect both T lymphocytes and cells of the human central nervous system, this could result in the expression of a novel opioid receptor that is only present in the human neurons and T lymphocytes.