Melanocortin receptor subtypes are expressed on cells in the oligodendroglial lineage and signal ACTH protection

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Adrenocorticotropic hormone (ACTH), a member of the melanocortin peptide family, is a primary component of ACTHAR gel, which is approved for the treatment of exacerbations of multiple sclerosis (MS) in adults. Although ACTH is widely assumed to work in shortening duration of relapses through an increase in endogenous corticosteroids via binding and signaling through melanocortin receptor 2 (MC2R) in the adrenals; other melanocortin receptors (MCR) are widely distributed throughout the organism including on inflammatory cells and cells of the central nervous system (CNS; Cone, 2006; Catania, Gatti, Colombo, & Lipton, 2004; Catania, 2008; Catina et al., 2010; Arnason, Berkovich, Catania, Lisak, & Zaidi, 2013). Melanocortin receptors are activated by ACTH and signal via adenylyl cyclase and multiple downstream pathways. We were the first to show that oligodendroglia (OL) express MC4R, and that ACTH increases proliferation and maturation of OL precursors (OPC) and increases the expansion of myelin‐like membrane sheets in culture (Benjamins, Nedelkoska, Bealmear, & Lisak, 2013; Benjamins, Nedelkoska, & Lisak, 2014). We have reported that ACTH1‐39 protects OL and OPC from cell death in vitro induced by mechanisms important in the pathogenesis of MS: 1) excitotoxicity through ionotropic glutamate receptors; 2) apoptosis, using staurosporine, a classic inducer of apoptosis; 3) inflammatory mediators, using quinolinic acid (QA), a product of tryptophan indoleamine metabolism; and 4) reactive oxygen species ROS) induced by H2O2 (Benjamins et al., 2014). Since OL and OPC express MC4R and protection can occur by direct activation of MC4R on OL and OPC, we sought to determine if OL express other types of melanocortin receptors, and if these receptors also functioned to protect OL.
Five subtypes of melanocortin receptors have been identified, and their distribution, function and pharmacology characterized, in part, by Cone (2006), Mountjoy (2010), and Dores et al. (2014). All five MCR are G protein‐coupled receptors and share a homologous 7‐membrane spanning domain, but differ in their N‐terminus and C‐terminus sequences (Dores et al., 2014). MC1R has been associated primarily with pigmentation, MC2R with glucocorticoid biosynthesis, MC3R and MC4R with energy homeostasis, and MC5R with exocrine gland regulation (Cone, 2006; Dores et al., 2014). However, each of the subtypes are widely distributed in various parts of the body where they appear to serve a variety of functions (Cone, 2006; Brzoska, Luger, Maaser, Abels, & Böhm, 2008; Catania, 2008; Arnason et al., 2013). The expression and function of the MCR1, 2, 3 and 5 subtypes in OL have not been previously investigated.
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