Abstract
Coincidentally, the release of this Research Topic in Frontiers in Endocrinology takes place 25 years after the discovery of the adrenocorticotropic hormone receptor (ACTHR) by Mountjoy and colleagues. In subsequent years, following the discovery of other types of mammalian melanocortin receptors (MCRs), ACTHR also became known as melanocortin type 2 receptor (MC2R). At present, five types of MCRs have been reported, all of which share significant sequence similarity at the amino acid level, and all of which specifically bind melanocortins (MCs)—a group of biologically active peptides generated by proteolysis of the proopiomelanocortin precursor. All MCs share an identical –H–F–R–W– pharmacophore sequence. α-Melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH) are the most extensively studied MCs and are derived from the same region. Essentially, α-MSH is formed from the first 13 amino acid residues of ACTH. ACTHR is unique among MCRs because it binds one sole ligand—ACTH, which makes it a very attractive research object for molecular pharmacologists. However, much research has failed, and functional studies of this receptor are lagging behind other MCRs. The reason for these difficulties has already been outlined by Mountjoy and colleagues in their publication on ACTHR coding sequence discovery where the Cloudman S91 melanoma cell line was used for receptor expression because it was a “more sensitive assay system.” Subsequent work showed that ACTHR could be successfully expressed only in endogenous MCR-expressing cell lines, since in other cell lines it is retained within the endoplasmic reticulum. The resolution of this methodological problem came in 2005 with the discovery of melanocortin receptor accessory protein, which is required for the formation of functionally active ACTHR. The decade that followed this discovery was filled with exciting research that provided insight into the molecular mechanisms underlying the action of ACTHR. The purpose of this review is to summarize the advances in this fascinating research field.
Highlights
Adrenocorticotropic hormone (ACTH), discovered in 1933 [1], is the primary regulator of aldosterone and corticosterone/cortisol production in mammalian adrenal glands [2,3,4,5]
The exception to this rule is γ-melanocyte-stimulating hormones (MSHs), but since it is not directly relevant to the main subject of this article, the reasons underlying this difference are not discussed [for details on molecular mechanisms underlying the action of this peptide see Ref. [12]]. α-Melanocyte-stimulating hormone (α-MSH) and ACTH are overlapping peptides since the aa sequence of the former is identical to the first 13 aa of the latter, because the former is the result of proteolytic cleavage of the latter (Figure 1)
It should be noted that this review only considers MRAP1 in relation to adrenocorticotropic hormone receptor (ACTHR), but the functions of this protein extend beyond formation of functionally active ACTHR [115, 119,120,121,122,123]
Summary
Adrenocorticotropic hormone (ACTH), discovered in 1933 [1], is the primary regulator of aldosterone and corticosterone/cortisol production in mammalian adrenal glands [2,3,4,5]. Experimental data suggest that this core sequence adopts a β-turn secondary structure in most MCs that is generally essential for ligand binding [11] The exception to this rule is γ-MSH, but since it is not directly relevant to the main subject of this article, the reasons underlying this difference are not discussed [for details on molecular mechanisms underlying the action of this peptide see Ref. It was concluded that the secondary structure of this motif is of paramount importance because it properly orients the other two motifs in relation to each other so that they can properly fit into the receptor-binding pocket(s) [27] This highly condensed introduction to ACTH, the ligand of ACTHR that is the main subject of this review, barely skims the enormous amount of knowledge acquired for mammalian and other lineages [6, 8, 10, 28,29,30,31,32,33,34,35,36,37]. We believe the core information provided here will be sufficient for interpretation of the research on the molecular mechanisms underlying the action of the adrenocorticotropic hormone receptor (ACTHR)
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