The Melanocortin (MC) Receptors are positively coupled to adenylate cyclase such that agonist-dependent activation induces intracellular cyclic adenosine monophosphate (cAMP) and subsequent activation of protein kinase A and cAMP response element binding. A core amino acid sequence, His-Phe-Arg-Trp (HFRW), within the MC peptides ACTH, α-MSH, β-MSH, and γ-MSH is key to receptor binding, activation, and biological activity. These biologically active fragments bind to MC receptors, five of which have been named and cloned in sequential order of discovery (MC1–5). They belong to the class of seven transmembrane group of G-protein–coupled receptors.
The melanocortin system comprises five melanocortin receptors (MCRs) that belong to the superfamily of G-protein coupled receptors (GPCRs) and are expressed differentially throughout the body. GPCRs represent the largest family of integral membrane proteins encoded by the human genome and detect a wide variety of ligands, including peptides, hormones, lipids, and nucleotides. Due to their involvement in many physiological processes, GPCRs are the target (directly or indirectly) of approximately 30-50% of current drugs. The five subtypes are melanocortin-1-receptor (MC1R), melanocortin-2-receptor (MC2R), melanocortin-3-receptor (MC3R), melanocortin-4-receptor (MC4R), and melanocortin-5-receptor (MC5R). These belong to class A of the GPCR super family, along with rhodopsin.
MCRs are among the shortest of the GPCRs. Hence the structures of the five receptor isoforms are closely related, and share some common features in binding endogenous agonists/antagonists. The endogenous melanocortin peptide agonists that activate MCRs are derived from the post translational modification of the same precursor polypeptide, pro-opiomelanocortin (POMC, 241 amino acids). These melanocortin ligands (ACTH, α-MSH, β-MSH, and γ-MSH) all contain a common core sequence of HFRW, considered the minimum sequence required to elicit a response from receptor binding.
The physiological functions mediated by the melanocortin receptors are regulated by endogenous agonists and antagonists. The endogenous agonists are α-, β- and γ-melanocyte stimulating hormones (MSH) and adrenocorticotropic hormone (ACTH) and are derived from a common precursor proopiomelanocortin hormone (POMC) through posttranslational processing. The melanocortin antagonists, agouti and agouti-related protein (AGRP), are the only two endogenous antagonists of GPCRs identified to date.
Endogenous Melanocortin Agonists
The endogenous melanocortin agonists are derived through posttranslational processing of their precursor proopiomelanocortin (POMC). POMC is expressed in the brain, skin, immune system and several other peripheral tissues. In the brain POMC is localized to the pituitary gland, the arcuate nucleus and the solitary tract. Posttranslational processing of POMC is tissue specific and results into the production of various bioactive peptides, including α-, β- and γ-MSH and ACTH by the prohormone convertases PC1 and PC2. In the anterior pituitary only prohormone convertase 1 (PC1) is expressed, but not PC2, resulting in the production of ACTH, and β-lipotropin. In contrast, the expression of PC2 within the hypothalamus may lead to the production of α-, β-, and γ-MSH and ACTH. For α-MSH Carboxypeptidase E further removes the C-terminal basic amino acids, followed by amidation and N-acetylation. All POMC derived melanocortin agonist peptides share a common message sequence of His-Phe-Arg-Trp which is postulated to be important for receptor recognition and activation.
Endogenous Melanocortin Antagonists
The Arg-Phe-Phe residues, which are conserved in both Agouti and AGRP, are believed to mimic the agonist Phe-Arg-Trp interactions with the receptors and are critical for antagonistic activity. Pharmacological characterization studies identified that Agouti antagonizes the skin MC1R and the brain MC3/4 receptors, whereas AGRP antagonizes only the brain MC3 and MC4 receptors. Further experimental evidence has been provided that Agouti and AGRP show inverse agonist activity in addition to competitive antagonism. Under physiological conditions, Agouti is expressed in hair follicles of the skin, while AGRP is expressed primarily in the hypothalamus of the brain and adrenal medulla.
Ralalage D E N G. Targeting melanocortin and cholecystokinin receptors via multivalent molecules bearing peptide ligands[M]. The University of Arizona, 2014.
Dehigaspitiya D C. Design, synthesis, and testing of multivalent compounds targeted to melanocortin receptors[M]. The University of Arizona, 2014.