Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction

The melanocortin 1 (MC1) receptor is mainly present in the periphery where it is, for example, found on melanoma cells and melanocytes and immune cells. In the CNS the MC1 receptor is present only on neurons in the periaqueductal grey matter of the mid brain, where it is thought to have a role in pain control.

The MC2 subtype is expressed in high quantities in the adrenal cortex, where it is activated by endogenous adrenocorticotropic hormone (ACTH) and controls steroidogenesis. Pharmacologically, the MC2 receptor differs substantially from the other MC receptors.

MC3 receptors are expressed in the regions of the CNS that overlap substantially with pro-opiomelanocortin (POMC)-expressing neuronal projections originating from the arcuate nucleus (ARC) of the hypothalamus, but the highest levels are colocalized with the cell bodies of the POMC neurons of the ARC. Expression of the MC3 receptor gene does not correlate with the quantity and distribution of the receptor protein in the brain, which suggests that the MC3 receptor might be axonally transported from its sites of expression. The MC3 receptor is also expressed in the periphery where it may have a role in haemodynamic control and immune-system regulations, although its immune function is also thought to occur in the CNS.

The MC4 receptor is mainly expressed in the CNS where it is found in virtually all areas, but it is also present in sensory neurons in the periphery. It has a major role in control of feeding behavior.

The MC5 receptor is expressed in many peripheral tissues, in particular the secretory epithelia of many exocrine glands where it affords secretory and trophic controls. The MC5 receptor may also be present in the CNS, but its function in this location is unknown.

Evidence exists to suggest that the different melanocyte-stimulating hormone (MSH) peptides, agouti and agouti-related protein (AgRP), are physiologically directed towards distinct melanocortin (MC) receptor subtypes.

From a pharmacological point of view, none of these endogenous mediators is uniquely selective as they show considerable overlap in their effects. Moreover, all the mediators exist in various forms owing to alternative metabolic transformations and these metabolites show distinct activity patterns. Some of these mediators may also act by other receptive systems, but the physiological relevance for such pathways still need to be clarified.

""

Using bioluminescence resonance energy transfer, melanocortin 1 (MC1) and MC3 receptors form constitutive homodimeric and heterodimeric or oligomeric complexes, whereas the MC4 receptor was shown to form homodimers.

A functional importance of MC4 oligomers was suggested when a dominant-negative effect of the D90N mutation on the wild-type MC4 was observed in a patient with early onset obesity. Co-expression of the mutated receptor with the wild-type MC4 receptor resulted in a drastic attenuation of the ability of the wild-type receptor to become activated by melanocyte-stimulating hormone (MSH). As fluorescence resonance energy transfer studies showed that the D90N mutant interacts with the wild-type MC4 receptor it appears that the mutated receptor prevents the normal receptor from acquiring its agonist-activated state upon binding of a-MSH.

Further investigation into the mechanisms and kinetics of agonist and inverse agonist binding to the MC4 receptor led to a model in which the subunits of the MC4 oligomers form mutually exclusive tandemly operated conformations. One of the subunits locks the ligand in a firmly bound state, while the ligand remains more loosely bound to the other subunit (Supplementary information S2). Kinetic data for the MC1 and MC3 receptors indicate that these also operate in a similar tandem fashion as the MC4 receptor.

Additionally, recent studies show that the MC4 receptor undergoes desensitization upon agonist stimulation, an action apparently caused by protein kinase A (PKA) and G-protein-coupled receptor kinase receptor phosphorylations and arrestin-conveyed receptor internalizations. Moreover, the MC4 receptor internalization occurred more efficiently with MSH peptide agonists than by some low-molecular-mass MC4 receptor agonists, despite their similar ability to stimulate cyclic AMP. Agouti-related protein (AgRP) is also capable of promoting arrestin-mediated internalization of the MC4 receptor.

These findings have major implications in drug discovery for the melanocortin receptors, as melanocortin receptor-active compounds seem to induce many different and independent types of actions on the melanocortin receptors. These different types of actions could result in distinct profiles for each drug with respect to its ability to cause agonistic/antagonistic/inverse agonistic actions, to stabilize melanocortin receptor oligomeric subunit conformations, and to promote receptor desensitization/internalization at each one of the different melanocortin receptor subtypes.

One other factor to be taken into consideration in melanocortin receptor signalling is their regulation by auxiliary proteins. One such protein is syndecan 3 (SDC3), which is a transmembrane protein with a large extracellular domain that is thought to bind to the N-terminal portion of AgRP and present it to the melanocortin receptors, thereby augmenting the effect of AgRP. The extracellular domain of SDC3, like other syndecans, can be cleaved by metalloproteinases by a process called ectodomain shedding. This would reduce the augmenting effects of the syndecans on AgRP. However, this hypothesis was recently challenged by observations that the N-terminal portion of AgRP appears to be completely cleaved off by post-translational processing before the release of AgRP. As the processed AgRP would not be capable of binding to SDC3 the observed correlations linking SDC3 with AgRP in feeding might be conicidental.

Another protein that is suggested to also have an auxiliary role in melanocortin signalling is attractin, a trans-membrane product of the mahogany (ATRN) gene. Attractin is thought to function as a low-affinity receptor for the agouti protein (but not for AgRP) and might act as a co-receptor in a similar way as proposed for SDC3.