Observations on the Evolution of the Melanocortin Receptor Gene Family: Distinctive Features of the Melanocortin-2 Receptor

Dores, Robert M.

doi:10.3389/fnins.2013.00028

Cited by 28 publications

(22 citation statements)

References 68 publications

(137 reference statements)

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“…This observation has led to the alternative speculation that the mc5r gene might have been the result of a local gene duplication of the mc4r gene (Vastermark & Shioth 2011). As a mc4r-like gene might have been the ancestral mcr gene (Dores 2013), the amino acid sequence identity data would suggest that there are selection pressures to minimize the accumulation of mutations in the mc5r gene relative to the mc2r gene. However, this conclusion seems counterintuitive given the critical role that MC2R plays in the HPA/HPI axis, and the importance of HPA/HPI axis to the physiological fitness of vertebrates (Crespi et al 2013).…”

Section: Mc5rmentioning

confidence: 99%

60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides

Dores

Liang

Davis

et al. 2016

Journal of Molecular Endocrinology

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The evolution of the melanocortin receptors (MCRs) is linked to the evolution of adrenocorticotrophic hormone (ACTH), the melanocyte-stimulating hormones (MSHs), and their common precursor pro-opiomelanocortin (POMC). The origin of the MCRs and POMC appears to be grounded in the early radiation of the ancestral protochordates. During the genome duplications that have occurred during the evolution of the chordates, the organization plan for POMC was established, and features that have been retained include, the high conservation of the amino acid sequences of α-MSH and ACTH, and the presence of the HFRW MCR activation motif in all of the melanocortin peptides (i.e. ACTH, α-MSH, β-MSH, γ-MSH, and δ-MSH). For the MCRs, the chordate genome duplication events resulted in the proliferation of paralogous receptor genes, and a divergence in ligand selectivity. While most gnathostome MCRs can be activated by either ACTH or the MSHs, teleost and tetrapod MC2R orthologs can only be activated by ACTH. The appearance of the accessory protein, MRAP1, paralleled the emergence of teleost and tetrapods MC2R ligand selectivity, and the dependence of these orthologs on MRAP1 for trafficking to the plasma membrane. The accessory protein, MRAP2, does not affect MC2R ligand selectivity, but does influence the functionality of MC4R orthologs. In this regard, the roles that these accessory proteins may play in the physiology of the five MCRs (i.e. MC1R, MC2R, MC3R, MC4R, and MC5R) are discussed.

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Section: Mc5rmentioning

confidence: 99%

60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides

Dores

Liang

Davis

et al. 2016

Journal of Molecular Endocrinology

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“…MC5R is believed to be the result of the local gene duplication event; however, the mcr gene that was duplicated to give rise to MC5R has been a debated topic in the literature. For alternative views on this subject, please see Klovins et al (2004a,b), Vastermark & Schiöth (2011), and Dores (2013).…”

Section: Overview Of Mcrs and Ligandsmentioning

confidence: 99%

MOLECULAR EVOLUTION OF GPCRS: Melanocortin/melanocortin receptors

Dores¹,

Londraville²,

Prokop³

et al. 2014

Journal of Molecular Endocrinology

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The melanocortin receptors (MCRs) are a family of G protein-coupled receptors that are activated by melanocortin ligands derived from the proprotein, proopiomelanocortin (POMC). During the radiation of the gnathostomes, the five receptors have become functionally segregated (i.e. melanocortin 1 receptor (MC1R), pigmentation regulation; MC2R, glucocorticoid synthesis; MC3R and MC4R, energy homeostasis; and MC5R, exocrine gland physiology). A focus of this review is the role that ligand selectivity plays in the hypothalamus/pituitary/adrenal-interrenal (HPA-I) axis of teleosts and tetrapods as a result of the exclusive ligand selectivity of MC2R for the ligand ACTH. A second focal point of this review is the roles that the accessory proteins melanocortin 2 receptor accessory protein 1 (MRAP1) and MRAP2 are playing in, respectively, the HPA-I axis (MC2R) and the regulation of energy homeostasis by neurons in the hypothalamus (MC4R) of teleosts and tetrapods. In addition, observations are presented on trends in the ligand selectivity parameters of cartilaginous fish, teleost, and tetrapod MC1R, MC3R, MC4R, and MC5R paralogs, and the modeling of the HFRW motif of ACTH(1-24) when compared with a-MSH. The radiation of the MCRs during the evolution of the gnathostomes provides examples of how the physiology of endocrine and neuronal circuits can be shaped by ligand selectivity, the intersession of reverse agonists (agouti-related peptides (AGRPs)), and interactions with accessory proteins (MRAPs).

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“…Syntenic analysis involves the comparison of the locations of orthologous or paralogous genes between chromosomes, within or among species, which facilitates more accurate analyses of the origins and relationships of individual peptide-7TMR families (Cerda-Reverter et al ., 2000; Lagerstrom et al ., 2005; Lee et al ., 2009; Kim et al ., 2011, 2012; Dores, 2013; Osugi et al ., 2014). However, small scale synteny analysis is only suitable for determining the evolutionary history of closely related families.…”

Section: Phylogeny and Synteny For Delineating Gene Family Emergencementioning

confidence: 99%

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors

Furlong

Seong

2017

Biomolecules & Therapeutics

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Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples.

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Observations on the Evolution of the Melanocortin Receptor Gene Family: Distinctive Features of the Melanocortin-2 Receptor

Cited by 28 publications

References 68 publications

60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides

60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides

MOLECULAR EVOLUTION OF GPCRS: Melanocortin/melanocortin receptors

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors

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