ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms?

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.

Pathological cyclic strain promotes proliferation of vascular smooth muscle cells via the ACTH/ERK/STAT3 pathway

“…Many studies have shown that the appropriate function of MC2R is closely related to the expression of MRAP . Therefore, changes in MRAP protein were examined in VSMCs before and after ACTH stimulation.…”

“…Many studies have shown that MC2R is differentially affected by MRAP isoforms. MRAP‐α provides higher sensitivity to ACTH, whereas higher cAMP response and membrane trafficking occur during co‐expression with MRAP‐β . MC2R is confined to the endoplasmic reticulum and cannot localize to the cell membrane when the cell lacks MRAP .…”

Регуляторные Пептиды Семейства Меланокортинов: Биосинтез, Рецепция, Биологические Эффекты

“…MСR2 рецепторы действуют совместно с МС2 добавочным протеином (MRAP), который абсолютно необходим для связывания с АКТГ и передачи сигнала [44]. MRAP имеет отдельный трансмембранный домен и форму антипараллельного гомодимера, стабильно ассоциированного с МСR2 в плазматической мембране [35,44]. Для активации МСR2 рецепторов особенно важны два участка АКТГ: His-Phe-Arg-Trp (АКТГ 6-9 ) и Lys-Lys-Arg-Arg-Pro (АКТГ [16][17][18][19][20] ).…”

Novel approaches to the design of bioavailable melanotropins

“…They can activate MC1R, MC3R, MC4R, and MC5R to trigger cAMP production without much selectivity. The MC2R is a special member of MCRs that can only be activated by adrenocorticotropic hormone [13], and thus would not be affected by peptide drugs based on MSHs. NDP-α-MSH (MT-I), the first generation of peptide drug targeting the melanocortin system, was developed using α-MSH as a template.…”