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.
Peptides function as chemical messengers throughout the body as neuropeptides (e.g., enkephalin), as peptide hormones (e.g., insulin), or both hormone and neuropeptide (e.g., oxytocin). Peptides affect a wide range of physiological and behavioral activities, including feeding and body weight regulation, sleep wake cycles and alertness, sexual activity and reproduction, pain, anxiety, fear, stress, depression, and the regulation of homeostasis of many parameters (blood glucose, temperature, etc.) (Fricker, 2012, Strand, 2003). Due to the large number of processes controlled by peptides, there has been considerable interest in the development of drugs that target peptide receptors. The most widely used drugs targeting neuropeptide receptors are the opiates, including natural products such as morphine as well as synthetics like fentanyl and oxycodone, all of which are commonly prescribed for the treatment of pain. Antagonists of the mu opioid receptor are used both to treat opioid overdose (naloxone) and to reduce the cravings of opioids, alcohol, nicotine, and food (naltrexone) (Aboujaoude and Salame, 2016, Greig and Keating, 2015, Sudakin, 2016). Other FDA-approved medications that target neuropeptide receptors include aprepitant, which is an antagonist of the substance P/neurokinin receptor NK1 and is used to treat nausea and vomiting, and suvorexant, an antagonist of the orexin receptors OX 1 and OX 2 that is used to treat insomnia (Preskorn, 2014). FDA-approved peptide analogs that target peptide hormone receptors include analogs of oxytocin (carbetocin), vasopressin (desmopressin), and glucagon-like peptide-1 (exenatide and others) (Fosgerau and Hoffmann, 2015, Janzen et al., 2016, Manning et al., 2008). Many more compounds are in development for a variety of indications, including drugs that target corticotropin-releasing factor CRF-1 receptors, neuropeptide Y-1, -2, and -5 receptors, melanocortin MC4R receptors, tachykinin receptors, neurotensin receptors, and others (Barak et al., 2016, Griebel and Beeske, 2012, Griebel and Holsboer, 2012, Jagoda et al., 2011, Kaspar and Reichert, 2013, Zorrilla and Koob, 2010). Most of these targets are G protein-coupled receptors (GPCRs), the largest class of receptors in the mammalian genome.
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All known GPCRs can be grouped into five main families based on consideration of amino acid sequence similarities (Fredriksson, Lagerstrom, Lundin, & Schioth, 2003). The families can be divided into groups and the groups further divided into sub-branches. In most cases these sequence-based divisions correspond to the types of ligands that the receptors recognize. Many of the putative GPCRs identified from analyses of the human genome or other nucleotide sequencing approaches did not have a
Unlike GPCRs, which are evolutionarily related and have regions with conserved amino acid sequences, there are no sequences conserved among all neuropeptides. Thus, novel neuropeptides cannot be identified from amino acid homology and alternate approaches have to be used. In this context, a biochemical approach was used to identify novel neuropeptide precursors in mice lacking carboxypeptidase E (CPE) activity (Che et al., 2001). This enzyme plays an important role in the biosynthesis of nearly
To identify receptors for proSAAS-derived peptides, we used a bioinformatics approach to select orphan GPCRs that were highly expressed in brain regions with high levels of proSAAS expression, such as the arcuate nucleus of the hypothalamus. Then, these receptors were individually tested for activation by the major proSAAS-derived peptides. These studies led to the identification of GPR171 as a receptor for b-LEN (Gomes et al., 2013). GPR171 (also known as H963) is highly conserved among mouse,
The modulation of neuropeptide signaling can occur via multiple mechanisms. One such mechanism is that of biased agonism. Some endogenous neuropeptides have been recently shown to function as biased agonists at GPCRs, differentially activating G protein and non-G protein coupled pathways (Wisler, Xiao, Thomsen, & Lefkowitz, 2014). For example, while Agouti-related protein (AgRP) functions as an MC4R antagonist when examining G protein signaling, it functions as a potent MC4R agonist activating
The recent advances in detection of peptides and proteins in various brain regions have led to the identification of a number of peptides and GPCRs. Using a combination of bioinformatics approaches to identify likely targets, followed by medium-throughput screening, we identified GPR83 and GPR171 as receptors for peptides PEN and LEN. Characterization of these receptor systems as well as other receptor systems in the hypothalamus has begun to reveal some of the intricacies of neuropeptide
The authors declare that there are no conflicts of interest.
We would like to thank Dr. Ivone Gomes for critical reading of this article. This work was supported in part by NIH grants DA008863 and NS026880 to L.A.D. and DA004494 to L.D.F.
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