General

The melanocortin system consists of five distinct receptors belonging to class A of seven-transmembrane G protein-coupled receptors (GPCRs), several agonists, and two endogenous inverse agonists, Agouti and Agouti-related peptide (AGRP) [4,41]. Melanocortin receptors are unique as they recognize both a family of peptide agonists encoded by the pro-opiomelanocortin (POMC) gene [27,39], and the inverse agonists, agouti and AGRP [13]. Melanocortin receptors have highly overlapping expression patterns as well as binding profiles in the brain and in the periphery [10,34] which is in line with the involvement of melanocortin peptides in numerous physiological functions such as energy homeostasis, pigmentation, sexual function, analgesia, inflammation, exocrine secretion, immunomodulation, and steroidogenesis [4,11,16,41,47-48]. The POMC gene is widely distributed and expressed both centrally and peripherally including skin [5,39]. POMC peptide is today known to be the precursor of 11 peptides (Pro-ACTH, β-LPH, N-POMC, JP, ACTH, α-MSH, β-MSH, γ-MSH, CLIP, γ-LPH, and β-Endorphin) several of which can be further biochemically modified into variants with distinct physiological functions [5,27,30,46]. The agouti gene is expressed primarily in follicular epithelial cells, and the AGRP gene is expressed in the arcuate nucleus of the hypothalamus and in the adrenal gland [45].

Five distinct receptors

There are five melanocortin receptors known at the present time, and each gene encodes a single protein version of each of the five receptors [34]. Almost 20 years after the sequencing of the POMC gene, the first melanocortin receptor gene, the MC₁ receptor (MC₁R), was sequenced [7-8,29] and the sequencing of MC₂R [7,29], MC₃R [17,33], MC₄R [17-18,28] and MC₅R [12,23,33,35,43] genes soon followed. Under NC-IUPHAR recommendations, the corresponding nomenclature would be MC₁, MC₂, MC₃, MC₄ and MC₅.

The MC₁ receptor (previously termed MSH-R) is expressed in melanocytes, keratinocytes, dermal fibroblasts, neutrophils, monocytes, B-lymphocytes, macrophages, endothelial cells, dendritic cells, glial cells, astrocytes and involved in the regulation of pigment production [42]. The MC₂ receptor (originally termed ACTH-R) is expressed in the adrenal cortex, adipose tissue, bone cells, and involved in the regulation of glucocorticoid hormone production [29]. The MC₃, MC₄, and MC₅ receptors had not been characterized as distinct pharmacological entities, but were cloned by homology to the MC₁ and MC₂ receptors [35]. They are distributed in both central and peripheral tissues and organs [5,10].

Functional characteristics

The physiology of the melanocortin receptors is simplified by the largely discrete distribution of the five receptors, and their functional roles are related to the responses mediated by the five known receptors [5,12,23]. The melanocortin system has a well-established role in the regulation of energy homeostasis [19,27,43], but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction [5,12,32,34]. A common molecular link between the various physiological conditions in which melanocortins play a role is their involvement in synaptic plasticity [24,26,37]. Melanocortin signaling coordinates synaptic adaptations in response to physiological stimuli such as hormonal or nutrient signals [5].

Pharmacology

Many of the well-characterized agonists and antagonists of the melanocortin receptors are peptides or proteins. The MC₁ receptor, in most species, is effectively an α-MSH receptor. The MC₂ receptor only recognizes the ACTH peptide. The MC₃ receptor is unique in that, while it recognizes all of the melanocortin peptides, it is the only MC receptor that binds γ-MSH with high affinity. The MC₄ receptor binds all of the melanocortin peptides, but only has high affinity for α-MSH and ACTH. The agouti peptide binds to the MC₁ and MC₄ receptors with high affinity in in vitro tests but, being normally expressed only in skin, only has access to the MC₁ receptor under physiological conditions [25]. The AGRP peptide is a high-affinity antagonist of the neural MC₃ receptor and the MC₄ receptor [15,31,38].

Future directions

During the past two decades, melanocortin peptides and receptors have received considerable attention regarding several CNS functions besides the regulation of energy control, and the multiple roles of the melanocortins represent an opportunity for therapeutic interventions. Molecular tools have allowed the identification of melanocortin receptors signaling in memory, reward, mood and nociception, and erectile function [1-2,5,9,14,21,44], among others. Interestingly, a recent study investigated the effects of intranasally administered HS014, a selective MC₄ receptor antagonist, and it resulted in marked resilience effects on the development of behavioral symptoms co-morbid with post-traumatic stress disorders [36]. Studies regarding the use of MC₄ receptor agonists on weight loss resulted in transient decreases in food intake (35%) and persistent weight loss in a nonhuman primate model [22]. Similarly, the involvement of the melanocortins in regulation of behavioral and emotional states, neuroprotection, inflammation and exocrine secretion are likely to spur the discovery of selective MC₁ and MC₅ receptor compounds [3,6,16,20,40].

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