"Are melanocortin receptors constitutively active in vivo?"

Abstract

Constitutive activity is defined as ligand-independent activity, resulting in the production of a second messenger, even in the absence of an agonist. There has been widespread acceptance of the concept of G-protein-coupled receptor constitutive activity, with this activity specifically blocked by inverse agonists, a particular class of ligands often previously characterised as merely antagonists. The melanocortin receptors are highly unusual because their physiological activity is mediated not by a single ligand but by a number of endogenous peptide ligands, with the ability to exhibit agonist, antagonist or potentially inverse agonist behaviour. It remains more contentious to what extent the demonstrable constitutive activity of melanocortin receptors, particularly those expressed within the central nervous system, has in (patho)physiological processes. This review examines evidence from animal and laboratory based studies, focussing particularly upon peripherally expressed melanocortin-1 receptors and centrally expressed melanocortin-4 receptors, to consider how recent insights into both receptor structure itself and the molecules know to play a role in melanocortin signalling continue to shape our understanding of melanocortin biology.

Keywords: Energy homeostasis; G protein coupled receptor; Melanocortin; POMC; Pigmentation.