Reinscheid R K, Nothacker H P, Civelli O
Institute for Cell Biochemistry and Clinical Neurobiology, University Hospital Eppendorf, Hamburg, Germany.
Results Probl Cell Differ. 1999;26:193-214. doi: 10.1007/978-3-540-49421-8_9.
The cloning of numerous orphan members from the supergene family of G protein-coupled receptors implies the existence of many as yet undiscovered neurotransmitters and neuropeptides. Recently, new technologies were developed to isolate natural ligands for orphan receptors, using the receptor as a biological sensor during the purification process. This manuscript will present the concept and technology of an approach which starts from a cloned receptor to ultimately describe the physiological functions of the transmitter system. This strategy inverts the classical order of biomedical research and was thus termed "reverse physiology". The first natural ligand isolated by this strategy is a peptide with significant similarity to the opioid peptides and has been named orphanin FQ or nociceptin (OFQ/NOC). Evidence for characterizing OFQ/NOC as a genuine neuropeptide will be reviewed. OFQ/NOC is biosynthetically derived from a larger precursor protein which may encode additional bioactive peptides. Since its discovery, a large number of studies have described numerous physiological functions of OFQ/NOC. Because of its relation to the opioid system, much attention has been focused on the involvement of OFQ/NOC in nociception, sometimes with controversial results. However, the pharmacological profile of the OFQ/NOC system suggests a clear separation from the opioids. The discovery of OFQ/NOC and the subsequent analyses of its physiological functions is an example which has already been followed by the identification of two other novel neuropeptides. The orphan receptor strategy holds a lot of promises for the postgenomic era, helping to fill the vast amount of sequence data with life.
从G蛋白偶联受体超基因家族中克隆出众多孤儿成员，这意味着存在许多尚未被发现的神经递质和神经肽。最近，人们开发了新技术来分离孤儿受体的天然配体，在纯化过程中把受体用作生物传感器。本论文将介绍一种方法的概念和技术，该方法从克隆的受体出发，最终描述递质系统的生理功能。这种策略颠倒了生物医学研究的经典顺序，因此被称为“逆向生理学”。通过这种策略分离出的首个天然配体是一种与阿片肽有显著相似性的肽，已被命名为孤啡肽FQ或痛敏肽（OFQ/NOC）。将对把OFQ/NOC鉴定为一种真正神经肽的证据进行综述。OFQ/NOC是通过生物合成从一种更大的前体蛋白衍生而来，该前体蛋白可能编码其他生物活性肽。自其被发现以来，大量研究描述了OFQ/NOC的众多生理功能。由于它与阿片系统的关系，OFQ/NOC在痛觉感受中的作用受到了很多关注，有时结果存在争议。然而，OFQ/NOC系统的药理学特征表明它与阿片类物质有明显区别。OFQ/NOC的发现以及随后对其生理功能的分析就是一个例子，随后又鉴定出了另外两种新型神经肽。孤儿受体策略在基因组学后时代有很大的前景，有助于用生命信息填补大量的序列数据。
