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      Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

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          Abstract

          The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization.

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          Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

          T Sakurai, A Amemiya, M Ishii … (1998)
          The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.
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            The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.

            L de Lecea, T S Kilduff, C Peyron … (1998)
            We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.
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              Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche.

              Akifumi Ootani, Xingnan Li, Eugenio Sangiorgi … (2009)
              The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both leucine-rich repeat-containing G protein-coupled receptor-5-positive (Lgr5(+)) and B lymphoma moloney murine leukemia virus insertion region homolog-1-positive (Bmi1(+)) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5(+) cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Acta Pharmacol Sin
                Journal ID (iso-abbrev): Acta Pharmacol. Sin
                Title: Acta Pharmacologica Sinica
                Publisher: Nature Publishing Group
                ISSN (Print): 1671-4083
                ISSN (Electronic): 1745-7254
                Publication date (Print): March 2012
                Publication date (Electronic): 27 February 2012
                Volume: 33
                Issue: 3
                Pages: 363-371
                Affiliations
                [1 ]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai 200241, China
                [2 ]Alkek Institute of Biosciences and Technology, Texas A&M University Health Science Center , Houston, Texas 77030, USA
                Author notes
                Article
                Publisher Item ID: aps2011210
                DOI: 10.1038/aps.2011.210
                PMC ID: 4077139
                PubMed ID: 22367282
                SO-VID: b58b6250-1f29-4132-933a-3b5274041ead
                Copyright © Copyright © 2012 CPS and SIMM
                History
                Date received : 12 December 2011
                Date accepted : 28 December 2011
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: g protein-coupled receptors,orphan gpcr,deorphanization,adhesion gpcr family,lgr subfamily,psgr,gpr48/lgr4
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: g protein-coupled receptors, orphan gpcr, deorphanization, adhesion gpcr family, lgr subfamily, psgr, gpr48/lgr4

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