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

Abstract

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.

Genomewide association studies of suicide attempts in US soldiers

“…The product of MRAP2 , M2CR accessory protein, supports M2CR cell surface expression necessary for the production of a functional ACTH-responsive melanocortin receptor [Chan et al 2009; Novoselova et al 2013]. MRAP2 is expressed in brain and adrenal tissue, where it is involved with neural control of energy homeostasis, possibly through Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affecting receptor signaling [Dores et al 2016; Jackson et al. 2015].…”

Plasticity for colour adaptation in vertebrates explained by the evolution of the genes pomc, pmch and pmchl

“…For Group 1 cyclostomes, we analysed the peptides that would arise from two genes with homology to pomc, pom (pro-opiomelanotropin) and poc (pro-opiocortin), which contain the ACTH and the α-MSH sequences, respectively (Heinig, Keeley, Robson, Sower, & Youson, 1995;Takahashi et al, 1995). Common to ACTH and all three MSH peptides is the presence of a His-Phe-Arg-Trp (HFRW) sequence, critical for binding and activation of MCRs (Dores et al, 2016;Schwyzer, 1977). We used this motif to align the various POMC peptides of the different taxonomic groups (Figure 6a).…”

“…α‐MSH is the hypophyseal hormone secreted from the pars intermedia pituitary into the circulation that mediates the background adaptation described initially in amphibians (Babák, ), and then in reptiles and some teleosts (Baker, Wilson, & Bowley, ; Okelo, ). α‐MSH is a 13‐amino acid (a.a.) peptide generated by the cleavage of the amino terminus of the adrenocorticotropic hormone (ACTH) peptide, which itself is processed from a larger precursor, proopiomelanocortin (POMC) (Dores, Liang, Davis, Thomas, & Petko, ; Liang, Reinick, Angleson, & Dores, ) (Figure ). α‐MSH induces pigment dispersion to darken the skin, and both pomc mRNA in the pars intermedia pituitary and plasma levels of α‐MSH increase in organisms with a black background (Baker et al, ; de Rijk, Jenks, & Wendelaar Bonga, ; Jenks, Overbeeke, & McStay, ).…”

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

“…Mutations in the HFRW or KKRRP motifs of ACTH (Liang et al 2013) in the POMC gene, or a non-functional PC1/3 in corticotropic cells (Seidah & Chretien 1999), abrogate the hypothalamo-pituitaryadrenal (HPA)-activating axis (Dores 2009, Dores et al 2014. The properties of MC2R are reviewed by Peng Loh and Robert Dores in this issue (Cawley et al 2016, Dores et al 2016.…”