Physiological roles of the melanocortin MC3 receptor

Abstract

The melanocortin MC 3 receptor remains the most enigmatic of the melanocortin receptors with regard to its physiological functions. The receptor is expressed both in the CNS and in multiple tissues in the periphery. It appears to be an inhibitory autoreceptor on proopiomelanocortin neurons, yet global deletion of the receptor causes an obesity syndrome. Knockout of the receptor increases adipose mass without a readily measurable increase in food intake or decrease in energy expenditure. And finally, no melanocortin MC 3 receptor null humans have been identified and associations between variant alleles of the melanocortin MC 3 receptor and disease remain controversial, so the physiological role of the receptor in humans remains to be determined. KeywordsMelanocortin-3 receptor; melanocortin MC3 receptor; Melanocortin; Obesity; γ-MSH; Proopiomelanocortin Structure and function of the receptorThe melanocortin MC 3 receptor belongs to the G-Protein Coupled Receptor family (Gantz et al., 1993;Roselli-Rehfuss et al., 1993). It is positively coupled to adenylyl cyclases through Gs and, upon activation, stimulates cAMP production. A few studies suggest that overexpressed melanocortin MC 3 receptor activation can also induce calcium release from intracellular stores (Kim et al., 2002b;Konda et al., 1994;Mountjoy et al., 2001). The mechanism of calcium release is unclear and the role of IP 3 generation is controversial (Kim et al., 2002a;Konda et al., 1994;Mountjoy et al., 2001). Based on the discrepancy observed in this signaling cascade when studied in different in-vitro models, it will be important to validate the activation of calcium signaling in melanocortin MC 3 receptor neurons in exvivo or in-vivo models. Another pathway activated downstream of melanocortin MC 3 receptor is the MAPK pathway. Indeed, Chai et al. showed that, in HEK293 cells transfected with the melanocortin MC 3 receptor, NDP-αMSH triggers a significant phosphorylation of ERK1/2 (Chai et al., 2007). In addition, they established that melanocortin MC 3 receptormediated MAPK activation is PI3K dependant and pertussis toxin sensitive (Chai et al., 2007). Interestingly, as with the melanocortin MC 4 receptor (Nijenhuis et al., 2001), the melanocortin MC 3 receptor was reported to have a constitutive activity (Nijenhuis et al., 2001) but the physiological relevance of this finding is still unclear. Importantly, the © 2010 Elsevier B.V. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , 1997). Like most G protein-coupled receptors, following activation, the melanocortin MC 3 receptor ...

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