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G protein-coupled receptors (GPCRs) are the largest family of cell membrane receptors in the human genome, comprisingw2% 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 numberof clinically useddrugs exert their biological effects via a GPCR, and orphanGPCRs 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

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