MOLECULAR EVOLUTION OF GPCRS: What we know and what the future holds

in Journal of Molecular Endocrinology
Author: Hubert Vaudry
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  • INSERM U982, International Associated Laboratory Samuel de Champlain, PRIMACEN, IRIB, University of Rouen, 76821 Mont-Saint-Aignan, France

Correspondence should be addressed to H Vaudry; Email: hubert.vaudry@univ-rouen.fr

G protein-coupled receptors (GPCRs) are the largest family of cell membrane receptors in the human genome, comprising ∼2% of human proteins. GPCRs are the target of a variety of signaling molecules such as peptide hormones, neuropeptides, chemokines, neurotransmitters, nucleotides, steroids, prostaglandins, cannabinoids, odorants, taste molecules, pheromones, and ions. A large number of clinically used drugs exert their biological effects via a GPCR, and orphan GPCRs provide valuable targets for the discovery of innovative drugs. Thus, it did not come as a surprise that the 2012 Nobel Prize in Chemistry was awarded to Robert J Lefkowitz and Brian K Kobila for their pioneer work on GPCR structures and functions.

The presence of GPCRs in the genome of all living organisms including bacteria, yeast, plants, invertebrates, and vertebrates shows the early evolutionary origin of these ubiquitous and versatile receptors. As a result of two major whole-genome duplication rounds during vertebrate evolution (Van de Peer et al. 2010), GPCRs have had the opportunity to explore new functions (neofunctionalization) while maintaining the ancient ones. In particular, in the case of peptide hormones, neuropeptides, and their GPCRs, these genome duplication events have played a dual role in the diversification of both ligands and receptors. These (neuro)peptide/GPCR pairs thus represent exceptional models for studying the process of co-evolution of ligand–receptor systems. The aim of this special issue was to assemble a comprehensive series of review articles that illustrate the molecular and functional evolution of diverse families of neuropeptide GPCRs that are involved in the regulation of essential physiological functions, i.e. reproduction, growth, stress response, energy, and water homeostasis.

Secretin, the first peptide hormone to be discovered (Bayliss & Starling 1902), belongs to a large family of related peptides, which encompasses VIP, PACAP, GHRH, and glucagon (Vaudry et al. 2009). It is now established that secretin acts as a neuropeptide that regulates vasopressin release and water homeostasis (Chu et al. 2009). Herein, the evolutionary origin of secretin and its receptor is discussed by Tam et al. (2014). Glucagon-like peptide 1 (GLP1) is also a member of the VIP–PACAP–glucagon superfamily of peptides. The paper by Hwang et al. (2014) describes the phylogenetic history of GLP1 and its receptor, GLP1R, which is regarded as a promising target for the development of new drugs aimed at treating type 2 diabetes and obesity. POMC-derived peptides exert their corticotropic and melanotropic activities through specific interaction with melanocortin receptors (Cone 2006). The paper by Dores et al. (2014) focuses on ligand selectivity of the five melanocortin receptors and the role that reverse agonists (i.e. agouti and AgRP) and accessory proteins are playing in melanocortin receptor functions. The CRH family comprises several neuropeptides including urotensin I, urocortins, and sauvagine (Vaughan et al. 1995). Orthologs of these peptides and their receptors have now been identified in invertebrates, notably in arthropods. In their review, Lovejoy et al. (2014) examine the co-evolution process of these peptide–GPCR systems and the diversity of their functions from insects to human. Somatostatin and urotensin II are two cyclic neuropeptides that have recently been shown to derive from a single ancestral gene (Tostivint et al. 2006). In this review, the authors discuss the evolutionary dynamics of somatostatin/urotensin II peptides and their receptors that have led to the unexpected complexity of these neuroendocrine systems (Tostivint et al. 2014). The identification of growth hormone secretagogue receptor (GHSR) and its natural ligand ghrelin is a striking example of the power of target base drug discovery, also termed ‘reverse pharmacology’, for the development of innovative therapeutic compounds (Kojima & Kangawa 2010). In their article, Kaiya et al. (2014) demonstrate that the remarkable simplicity of the ghrelin–GHSR system of tetrapods (i.e. one ligand and one receptor) markedly contrasts with the complexity of this system in teleosts. Kisspeptin, a member of the RFamide peptide superfamily, plays a critical role in sexual differentiation and reproduction (de Roux et al. 2003, Seminara et al. 2003). The paper by Pasquier et al. (2014) highlights the tumultuous history of kisspeptins and their receptors during vertebrate evolution. 26RFa/QRFP is another RFamide peptide that was initially identified as an orexigenic neuropeptide (Chartrel et al. 2003). The article by Ukena et al. (2014) provides a complete overview of the molecular and functional evolution of 26RFa and its receptor, called QRFPR, from lamprey to mammals.

It is our hope that this issue will become a major reference for researchers working on the evolutionary aspects of GPCRs and their peptide ligands.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this editorial.

Funding

This editorial was supported by the EU grant through the Peptide Research Network of Excellence (PeReNe) project.

Acknowledgements

The author wishes to express gratitude to the authors who have contributed to this special Thematic Review issue and to the reviewers who helped them in reaching the highest quality standards. The authors are deeply indebted to the Journal of Molecular Endocrinology team for their invaluable support and to Mrs Catherine Beau for her skillful secretarial assistance.

References

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  • Chartrel N, Dujardin C, Anouar Y, Leprince J, Decker A, Clerens S, Do-Régo JC, Vandesande F, Llorens-Cortes C & Costentin J 2003 Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. PNAS 100 1524715252. (doi:10.1073/pnas.2434676100).

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  • Chu JY, Lee LT, Lai CH, Vaudry H, Chan YS, Yung WH & Chow BK 2009 Secretin as a neurohypophysial factor regulating body water homeostasis. PNAS 106 1596115966. (doi:10.1073/pnas.0903695106).

    • Search Google Scholar
    • Export Citation
  • Cone RD 2006 Studies on the physiological functions of the melanocortin system. Endocrine Reviews 27 736749. (doi:10.1210/er.2006-0034).

  • Dores RM, Londraville RL, Prokop J, Davis P & Dewey N 2014 MOLECULAR EVOLUTION OF GPCRS: Melanocortin/melanocortin receptors. Journal of Molecular Endocrinology 52 2942. (doi:10.1530/JME-14-0050).

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  • Hwang J-I, Yun S, Moon MJ, Park CR & Seong JY 2014 MOLECULAR EVOLUTION OF GPCRS: GLP-1/GLP-1 receptors. Journal of Molecular Endocrinology 52 T15T27. (doi:10.1530/JME-13-0137).

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  • Kaiya H, Kangawa K & Miyazato M 2014 MOLECULAR EVOLUTION OF GPCRS: Ghrelin/ghrelin receptors. Journal of Molecular Endocrinology 52 87100. (doi:10.1530/JME-13-0175).

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  • Kojima M & Kangawa K 2010 Ghrelin: more than endogenous growth hormone secretagogue. Annals of the New York Academy of Sciences 1200 140148. (doi:10.1111/j.1749-6632.2010.05516.x).

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  • Lovejoy DA, Chang B, Lovejoy N & del Castillo J 2014 MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors. Journal of Molecular Endocrinology 52 4360. (doi:10.1530/JME-13-0238).

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  • Pasquier J, Kamech N, Lafont A-G, Vaudry H, Rousseau K & Dufour S 2014 MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors. Journal of Molecular Endocrinology 52 101117. (doi:10.1530/JME-13-0224).

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  • de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL & Milgrom E 2003 Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. PNAS 100 1097210976. (doi:10.1073/pnas.1834399100).

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  • Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM & Hendrick AG 2003 The GPR54 gene as a regulator of puberty. New England Journal of Medicine 349 16141627. (doi:10.1056/NEJMoa035322).

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    • Export Citation
  • Tam JKV, Lee LTO, Jin J & Chow BKC 2014 MOLECULAR EVOLUTION OF GPCRS: Secretin/secretin receptors. Journal of Molecular Endocrinology 52 T1T14. (doi:10.1530/JME-13-0259).

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  • Tostivint H, Joly L, Lihrmann I, Parmentier C, Lebon A, Morisson M, Calas A, Ekker M & Vaudry H 2006 Comparative genomics provides evidence for close evolutionary relationships between the urotensin II and somatostatin gene families. PNAS 103 22372242. (doi:10.1073/pnas.0510700103).

    • Search Google Scholar
    • Export Citation
  • Tostivint H, Daza DO, Bergqvist CA, Quan FB, Bougerol M, Lihrmann I & Larhammar D 2014 MOLECULAR EVOLUTION OF GPCRS: Somatostatin/urotensin II receptors. Journal of Molecular Endocrinology 52 6186. (doi:10.1530/JME-13-0274).

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    • Export Citation
  • Ukena K, Osugi T, Leprince J, Vaudry H & Tsutsui K 2014 MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103. Journal of Molecular Endocrinology 52 119131. (doi:10.1530/JME-13-0207).

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  • Van de Peer Y, Maere S & Meyer A 2010 Correspondence: 2R or not 2R is not the question anymore. Nature Reviews. Genetics 11 166. (doi:10.1038/nrg2600-c2)doi:10.1038/nrg2600-c2.

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    • Export Citation
  • Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H & Galas L 2009 Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacological Reviews 61 283357. (doi:10.1124/pr.109.001370).

    • Search Google Scholar
    • Export Citation
  • Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D & Rivier C 1995 Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378 287292. (doi:10.1038/378287a0).

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This editorial accompanies eight papers that form part of a thematic review section on the Molecular Evolution of GPCRs. The Guest Editor for this section was Hubert Vaudry, European Institute for Peptides Research, University of Rouen, France.

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  • Bayliss WM & Starling EH 1902 The mechanism of pancreatic secretion. Journal of Physiology 28 325353.

  • Chartrel N, Dujardin C, Anouar Y, Leprince J, Decker A, Clerens S, Do-Régo JC, Vandesande F, Llorens-Cortes C & Costentin J 2003 Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. PNAS 100 1524715252. (doi:10.1073/pnas.2434676100).

    • Search Google Scholar
    • Export Citation
  • Chu JY, Lee LT, Lai CH, Vaudry H, Chan YS, Yung WH & Chow BK 2009 Secretin as a neurohypophysial factor regulating body water homeostasis. PNAS 106 1596115966. (doi:10.1073/pnas.0903695106).

    • Search Google Scholar
    • Export Citation
  • Cone RD 2006 Studies on the physiological functions of the melanocortin system. Endocrine Reviews 27 736749. (doi:10.1210/er.2006-0034).

  • Dores RM, Londraville RL, Prokop J, Davis P & Dewey N 2014 MOLECULAR EVOLUTION OF GPCRS: Melanocortin/melanocortin receptors. Journal of Molecular Endocrinology 52 2942. (doi:10.1530/JME-14-0050).

    • Search Google Scholar
    • Export Citation
  • Hwang J-I, Yun S, Moon MJ, Park CR & Seong JY 2014 MOLECULAR EVOLUTION OF GPCRS: GLP-1/GLP-1 receptors. Journal of Molecular Endocrinology 52 T15T27. (doi:10.1530/JME-13-0137).

    • Search Google Scholar
    • Export Citation
  • Kaiya H, Kangawa K & Miyazato M 2014 MOLECULAR EVOLUTION OF GPCRS: Ghrelin/ghrelin receptors. Journal of Molecular Endocrinology 52 87100. (doi:10.1530/JME-13-0175).

    • Search Google Scholar
    • Export Citation
  • Kojima M & Kangawa K 2010 Ghrelin: more than endogenous growth hormone secretagogue. Annals of the New York Academy of Sciences 1200 140148. (doi:10.1111/j.1749-6632.2010.05516.x).

    • Search Google Scholar
    • Export Citation
  • Lovejoy DA, Chang B, Lovejoy N & del Castillo J 2014 MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors. Journal of Molecular Endocrinology 52 4360. (doi:10.1530/JME-13-0238).

    • Search Google Scholar
    • Export Citation
  • Pasquier J, Kamech N, Lafont A-G, Vaudry H, Rousseau K & Dufour S 2014 MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors. Journal of Molecular Endocrinology 52 101117. (doi:10.1530/JME-13-0224).

    • Search Google Scholar
    • Export Citation
  • de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL & Milgrom E 2003 Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. PNAS 100 1097210976. (doi:10.1073/pnas.1834399100).

    • Search Google Scholar
    • Export Citation
  • Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM & Hendrick AG 2003 The GPR54 gene as a regulator of puberty. New England Journal of Medicine 349 16141627. (doi:10.1056/NEJMoa035322).

    • Search Google Scholar
    • Export Citation
  • Tam JKV, Lee LTO, Jin J & Chow BKC 2014 MOLECULAR EVOLUTION OF GPCRS: Secretin/secretin receptors. Journal of Molecular Endocrinology 52 T1T14. (doi:10.1530/JME-13-0259).

    • Search Google Scholar
    • Export Citation
  • Tostivint H, Joly L, Lihrmann I, Parmentier C, Lebon A, Morisson M, Calas A, Ekker M & Vaudry H 2006 Comparative genomics provides evidence for close evolutionary relationships between the urotensin II and somatostatin gene families. PNAS 103 22372242. (doi:10.1073/pnas.0510700103).

    • Search Google Scholar
    • Export Citation
  • Tostivint H, Daza DO, Bergqvist CA, Quan FB, Bougerol M, Lihrmann I & Larhammar D 2014 MOLECULAR EVOLUTION OF GPCRS: Somatostatin/urotensin II receptors. Journal of Molecular Endocrinology 52 6186. (doi:10.1530/JME-13-0274).

    • Search Google Scholar
    • Export Citation
  • Ukena K, Osugi T, Leprince J, Vaudry H & Tsutsui K 2014 MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103. Journal of Molecular Endocrinology 52 119131. (doi:10.1530/JME-13-0207).

    • Search Google Scholar
    • Export Citation
  • Van de Peer Y, Maere S & Meyer A 2010 Correspondence: 2R or not 2R is not the question anymore. Nature Reviews. Genetics 11 166. (doi:10.1038/nrg2600-c2)doi:10.1038/nrg2600-c2.

    • Search Google Scholar
    • Export Citation
  • Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H & Galas L 2009 Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacological Reviews 61 283357. (doi:10.1124/pr.109.001370).

    • Search Google Scholar
    • Export Citation
  • Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D & Rivier C 1995 Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378 287292. (doi:10.1038/378287a0).

    • Search Google Scholar
    • Export Citation