Civelli O, Nothacker H P, Reinscheid R
Department of Pharmacology, University of California, Irvine 92697-4625, USA.
Crit Rev Neurobiol. 1998;12(3):163-76. doi: 10.1615/critrevneurobiol.v12.i3.10.
The search for novel neurotransmitters and neuropeptides has been recently revolutionized by the development of a purification strategy based on orphan G protein-coupled receptors, cloned receptors for which no natural ligands are known. This strategy uses the orphan receptor as bait to identify its natural ligand. This article will review the discovery of the first natural ligand isolated following this strategy. This ligand is a peptide that shares some striking sequence similarity to the opioid peptides and has been named Orphanin FQ or Nociceptin (OFQ/NOC). The discovery of OFQ/NOC will be described as one example of the use of orphan receptors in identifying novel neurotransmitters and neuropeptides, an example that has already been followed in the identification of other novel neuropeptides. After reviewing the conceptual and technological basis of the strategy and its successful first application, we discuss the criteria used to validate OFQ/NOC as the natural ligand of the orphan receptor and as a genuine neuropeptide. We also discuss the importance and implications of discovering OFQ/NOC mode of synthesis, which is synthesized as expected in the form of a larger polypeptide precursor, which in turn raises the question of the existence of other OFQ/NOC-related peptides. We then present an overview of the numerous studies that have blossomed after the OFQ/NOC discovery and describe the numerous physiological roles that have already been attributed to OFQ/NOC, and in particular the controversy regarding its involvement in pain perception. Because of the similarities between the OFQ/NOC and opioid systems, we also discuss overlaps between these systems and present evidence favoring a pharmacological separation between these systems. We finish by outlining the power of the orphan receptor strategy and by discussing some of its pitfalls.
基于孤儿G蛋白偶联受体开发的纯化策略最近彻底改变了新型神经递质和神经肽的研究。孤儿G蛋白偶联受体是指那些已被克隆，但天然配体未知的受体。该策略以孤儿受体为诱饵来鉴定其天然配体。本文将回顾按照此策略分离出的首个天然配体的发现过程。这种配体是一种肽，与阿片肽在序列上有一些显著的相似性，被命名为孤啡肽FQ或痛敏肽（OFQ/NOC）。OFQ/NOC的发现将作为孤儿受体在鉴定新型神经递质和神经肽中的一个应用实例来描述，在鉴定其他新型神经肽时也采用了这一实例。在回顾该策略的概念和技术基础及其首次成功应用之后，我们讨论了用于验证OFQ/NOC作为孤儿受体天然配体以及作为一种真正神经肽的标准。我们还讨论了发现OFQ/NOC合成方式的重要性和意义，它是以一种更大的多肽前体形式按预期合成的，这反过来又引发了是否存在其他与OFQ/NOC相关肽的问题。然后，我们概述了在OFQ/NOC发现之后蓬勃开展的众多研究，并描述了已归因于OFQ/NOC的众多生理作用，特别是关于其在痛觉感知中作用的争议性。由于OFQ/NOC和阿片系统之间存在相似性，我们还讨论了这些系统之间的重叠，并提供了支持这些系统在药理学上分离的证据。我们最后概述了孤儿受体策略的作用，并讨论了其一些缺陷
