Neuropeptides are the largest class of intercellular signaling molecules, contributing to a wide variety of physiological processes. Neuropeptide receptors are therapeutic targets for a broad range of drugs, including medications to treat pain, addiction, sleep disorders, and nausea. In addition to > 100 peptides with known functions, many peptides have been identified in mammalian brain for which the cognate receptors have not been identified. Similarly, dozens of “orphan” G protein-coupled receptors have been identified in the mammalian genome. While it would seem straightforward to match the orphan peptides and receptors, this is not always easily accomplished. In this review we focus on peptides named PEN and big LEN, which are among the most abundant neuropeptides in mouse brain, and their recently identified receptors: GPR83 and GPR171. These receptors are co-expressed in some brain regions and are able to interact. Because PEN and big LEN are produced from the same precursor protein and co-secreted, the interaction of GPR83 and GPR171 is physiologically relevant. In addition to interactions of these two peptides/receptors, PEN and LEN are co-localized with neuropeptide Y and Agouti-related peptide in neurons that regulate feeding. In this review, using these peptide receptors as an example, we highlight the multiple modes of regulation of receptors and present the emerging view that neuropeptides function combinatorially to generate a network of signaling messages. The complexity of neuropeptides, receptors, and their signaling pathways is important to consider both in the initial deorphanization of peptides and receptors, and in the subsequent development of therapeutic applications.

神经肽是细胞间信号分子中最大的一类，有助于多种生理过程。神经肽受体是多种药物的治疗靶标，包括治疗疼痛，成瘾，睡眠障碍和恶心的药物。除了具有已知功能的> 100种肽外，在哺乳动物脑中还鉴定了许多尚未鉴定出同源受体的肽。同样，在哺乳动物基因组中已经鉴定出数十种“孤儿” G蛋白偶联受体。虽然看起来很容易匹配孤儿肽和受体，但这并不总是容易实现的。在这篇综述中，我们重点研究名为PEN和大LEN的肽，它们是小鼠脑中最丰富的神经肽，以及它们最近鉴定的受体：GPR83和GPR171。这些受体在某些大脑区域共表达，并能够相互作用。由于PEN和大LEN由相同的前体蛋白产生并共同分泌，因此GPR83和GPR171的相互作用在生理上是相关的。除了这两种肽/受体的相互作用外，PEN和LEN在调节进食的神经元中与神经肽Y和Agouti相关肽共定位。在这篇综述中，以这些肽受体为例，我们重点介绍了受体的多种调节模式，并提出了神经肽组合发挥功能以生成信号传递网络的新兴观点。神经肽，受体及其信号传导途径的复杂性对于在肽和受体的最初去孤儿化中都需要考虑，