Opioid Binding to U51: A Human herpes Virus Protein

描述：（申请人提供） 人疱疹病毒（HHV）-6和HHV-7是感染人的病毒， 中枢神经系统和T淋巴细胞。HHV-6，与 HHV-7在遗传水平上经常与疾病相关，特别是 免疫功能低下的人和艾滋病患者。HHV-6和HHV-7 表达7-跨膜G蛋白偶联受体U 51， 被鉴定为阿片受体同源物，共享超过50%的 与κ阿片受体序列相似HHV-6和-7 U 51共享 与κ、μ和δ阿片受体的序列相似性大于 与任何其他克隆蛋白质。HHV-6 U 51是一种趋化因子受体， 趋化因子RANTES和其它β趋化因子，如嗜酸性粒细胞趋化因子、单核细胞趋化因子 趋化蛋白1、3和4。而HHV-7 U 51可能与β 趋化因子，这还没有得到明确的证明，将在 拟议的研究，这将检查阿片类药物与两者的相互作用 HHV-6 U 51和HHV-7 U 51。要测试的总体假设是，U 51 一种结合趋化因子的蛋白质，是人类κ阿片样物质的同系物 受体，将结合一些阿片类药物，这些阿片类药物将激活U 51 受体，并调节RANTES的结合和功能。以下 将测试具体目标：1）确定阿片类药物是否会抑制结合 趋化因子[125 I]RANTES对HHV-6和HHV-7 U 51蛋白的影响; 2）确定 如果阿片类药物激活U 51蛋白，如用[35 S] GTP γ S测量的， 结合测定;和3）确定阿片类药物是否调节RANTES诱导的 刺激[35 S] GTP γ S结合。这项提案有资格被削减 边缘基础研究奖，因为如果阿片类药物结合到趋化因子受体 U 51，这一发现将证明两种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， 人类中枢神经系统的细胞，这可能会导致表达 一种新的阿片受体，只存在于人类神经元和T 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.