Pro-Opiomelanocortin
It seems likely that pro-opiomelanocortin (POMC) appeared early on in vertebrate evolution, with primitive jawless fish having a POMC coding sequence very similar to that seen in higher mammals. In humans, the POMC gene consists of 3 exons, and although POMC mRNA can be detected in a number of tissues, the gene is expressed at physiologically significant levels in a limited range of tissues. These include the skin, corticotrophs of the anterior pituitary, the hypothalamus, and the brainstem.
POMC is an archetypal polypeptide precursor, with the 241–amino acid propeptide being functionally inert. The name "melanocortin" derives from the early studies of peptides extracted from pituitary glands that demonstrated that these peptides were able to bring about dramatic changes in melanin pigmentation and stimulate glucocorticoid production. This family of peptides possess structural similarity with a characteristic invariant tetrapeptide motif (His-Phe-Arg-Trp) at their core.
Melanocortin Receptors
The actions of the melanocortin peptides are mediated through a family of 5 melanocortin receptors (MC1-R through MC5-R). These receptors show considerable homology, all being G protein–coupled, 7-transmembrane domain receptors. MC1-R is expressed on a range of cell types within the skin, including melanocytes, keratinocytes, and cells of the immune system. MC2-R is the classic ACTH receptor, expressed in the cortex of the adrenal gland. MC2-R binds only ACTH and has no affinity for the other melanocortin peptides, although ACTH itself is recognized by the other 4 melanocortin receptors. The MC3-R is expressed in the brain, chiefly within the hypothalamus, cortex, thalamus, and limbic system. It has also been detected in the gut, placenta, kidney, and heart. MC4-R is expressed widely throughout the mammalian central nervous system. It is highly expressed in regions of the hypothalamus known to be involved in the control of energy homeostasis and is found within the brainstem and spinal cord. MC5-R is expressed more ubiquitously in many peripheral tissues but appears to have a role in pheromone- and sebum-producing exocrine glands.
Central Melanocortin System
Contained within the arcuate nucleus of the hypothalamus are 2 separate populations of neurons that express POMC or both NPY and agouti-related protein (AgRP), which is a potent melanocortin antagonist at the MC3 and 4 receptors. From the arcuate nucleus, POMC neurons project to many other regions of the brain, including other hypothalamic regions such as the paraventricular nucleus that are involved in energy homeostasis (paraventricular nucleus). Caudally, projections extend to the thalamus and the medial amygdala; POMC neurons also send descending projections to the brainstem and spinal cord. It is these arcuate neurons, together with their downstream second-order neurons expressing MC3-R and MC4-R, that make up the central melanocortin system. The fed state is characterized by increased POMC neuronal activity with inhibition of AgRP neurons. This increase in melanocortin tone in regions of the brain expressing MC4-R decreases food intake and increases energy expenditure. In contrast, states of negative energy balance such as fasting are characterized by inactivation of POMC neurons (therefore reducing melanocortin levels) but stimulation of AgRP activity. The resultant decrease in MC4-R signaling stimulates feeding and reduces energy expenditure.
An intact central melanocortin signaling pathway is critical for normal energy homoeostasis, with defects in synthesis, processing, and action of POMC peptides resulting in obesity. For example, genetic deletion of MC4-R in mice and humans results in severe hyperphagic obesity, with an increase in both fat and lean mass. Indeed, MC4-R mutations are responsible for up to 5% of cases of severe childhood obesity and up to 2.5% of adult obesity. A study of the general population in the United Kingdom suggested a mutational frequency of 1 in 1000, making MC4-R deficiency one of the most common single-gene disorders. Of course, this still means that the majority of obese people cannot ascribe their obesity to defective melanocortin receptor functioning, with many complex interactions between environment and genes yet to be untangled, but these studies have played a major role in highlighting the importance of this pathway in human physiology.
Melanocortin receptors are G protein-coupled receptors
There are five known members of the melanocortin receptor system each with differing specificities for melanocortins]MC1R. MC1R is associated with pigmentation genetics. MC2R. MC2R is also known as the ACTH receptor or corticotropin receptor because it is specific for ACTH alone.
MC3R. not much known MC4R. Defects in MC4R are a cause of autosomal dominant obesity, accounting for 6% of all cases of early-onset obesity.
MC5R. still lots unknown
Selective Ligands
Several selective ligands for the melanocortin receptors are known, and some synthetic compounds have been investigated as potential tanning, anti-obesity and aphrodisiac drugs, with tanning effects mainly from stimulation of MC1, while anorectic and aphrodisiac effects appear to involve both MC3 and MC4. MC1, MC3 and MC4 are widely expressed in the brain, and are also thought to be responsible for effects on mood and cognition.
Structure, function and regulation of the melanocortin receptors.
2011
Melanocortin receptors belong to the seven-transmembrane (TM) domain proteins that are coupled to G-proteins and signaled through intracellular cyclic adenosine monophosphate. Many structural features conserved in other G-protein coupled receptors (GPCRs) are found in the melanocortin receptors. There are five melanocortin receptor subtypes and each of the melanocortin receptor subtypes has a different pattern of tissue expression and has its own profile regarding the relative potency of different melanocortin peptides. ?-, ?-, and ?-MSH and ACTH are known endogenous agonist ligands for the melanocortin receptors. Agouti and AgRP are the only known naturally occurring antagonists of the melanocortin receptors. We have examined the molecular basis of all five human melanocortin receptors for different ligand binding affinities and potencies using chimeric and mutated receptors. Our studies indicate that human melanocortin MC(1) receptor, human melanocortin MC(3) receptor, human melanocortin MC(4) receptor and human melanocortin MC(5) receptor utilize orthosteric sites for non selective agonists, ?-MSH and NDP-??-MSH, high affinity binding and utilize allosteric sites for selective agonist or antagonist binding. Furthermore, our results indicate that molecular determinants of human melanocortin MC(2) receptor for ACTH binding and signaling are different from that of other melanocortin receptors. Many studies also indicate that agonists can induce different conformation changes of melanocortin receptors, which then lead to the activation of different signaling pathways, even when the expression level of receptor and the strength of stimulus-response coupling are the same. This finding may provide new information for the design of drugs for targeting melanocortin receptors.
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