Abstract
The melanocortin receptors (MCRs) are a gene family in the rhodopsin class of G protein-coupled receptors. Based on the analysis of several metazoan genome databases it appears that the MCRs are only found in chordates. The presence of five genes in the family (i.e., mc1r, mc2r, mc3r, mc4r, mc5r) in representatives of the tetrapods indicates that the gene family is the result of two genome duplication events and one local gene duplication event during the evolution of the chordates. The MCRs are activated by melanocortin ligands (i.e., ACTH, α-MSH, β-MSH, γ-MSH, δ-MSH) which are all derived from the polypeptide hormone/neuropeptide precursor, POMC, and as a result the functional evolution of the MCRs is intimately associated with the co-evolution of POMC endocrine and neuronal circuits. This review will consider the origin of the MCRs, and discuss the evolutionary relationship between MC2R, MC5R, and MC4R. In addition, this review will analyze the functional evolution of the mc2r gene in light of the co-evolution of the MRAP (Melanocortin-2 Receptor Accessory Protein) gene family.
Highlights
An analysis of tetrapod genomes indicates that the melanocortin receptors (MCRs) are a family of five G protein-coupled receptors (GPCRs) genes that have been implicated in the mediation of integument pigmentation, appetite regulation, glucocorticoid synthesis, and exocrine gland secretion (Gantz and Fong, 2003; Cone, 2006)
The functional evolution of at least some of the MCRs is tied to the co-evolution of two other gene families; the Melanocortin-2 Receptor Accessory Protein (MRAP) gene family (Metherell et al, 2005; Hinkle and Sebag, 2009; Webb and Clark, 2010; Liang et al, 2011; Vastermark and Schiöth, 2011), and the AGRP/ASIP gene family (Vastermark and Schiöth, 2011)
The evolution of the MCRs is intertwined with the co-evolution of the ligand-encoding POMC gene, the accessory protein MRAP genes, and the inverse agonist AGRP/ASIP genes
Summary
An analysis of tetrapod (amphibians, reptiles, birds, and mammals) genomes indicates that the melanocortin receptors (MCRs) are a family of five G protein-coupled receptors (GPCRs) genes (i.e., mc1r, mc2r, mc3r, mc4r, mc5r) that have been implicated in the mediation of integument pigmentation, appetite regulation, glucocorticoid synthesis, and exocrine gland secretion (Gantz and Fong, 2003; Cone, 2006). Another feature of the melanocortin network that has been rigorously retained is the differential posttranslational processing of the POMC precursor by the endoproteolytic cleavage enzymes, prohormone convertase 1 (anterior pituitary) and prohormone hormone convertase 2 (intermediate pituitary; Seidah and Chrétien, 1999) Applying this same scenario to the evolution of the melanocortin receptor genes (Figure 2B), the lamprey genome may contain two additional MCRs. the unique sequence motifs in the MC1R ortholog (MCaR) and the MC4R ortholog (MCbR) may be more derived features than ancestral features. A corollary to this assumption is that MCR paralogs would contain a “MC4R” signature; that is, sets of amino acid motifs derived from the proposed ancestral MC4R gene In this scenario a MC2R/MC5R gene in FIGURE 3 | Revised scheme for the evolution of the melanocortin receptors.
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