Abstract
The melanocortin-4 receptor (MC4R) is a class A G protein-coupled receptor (GPCR), essential for regulation of appetite and metabolism. Pathogenic inactivating MC4R mutations are the most frequent cause of monogenic obesity, a growing medical and socioeconomic problem worldwide. The MC4R mediates either ligand-independent or ligand-dependent signaling. Agonists such as α-melanocyte-stimulating hormone (α-MSH) induce anorexigenic effects, in contrast to the endogenous inverse agonist agouti-related peptide (AgRP), which causes orexigenic effects by suppressing high basal signaling activity. Agonist action triggers the binding of different subtypes of G proteins and arrestins, leading to concomitant induction of diverse intracellular signaling cascades. An increasing number of experimental studies have unraveled molecular properties and mechanisms of MC4R signal transduction related to physiological and pathophysiological aspects. In addition, the MC4R crystal structure was recently determined at 2.75 Å resolution in an inactive state bound with a peptide antagonist. Underpinned by structural homology models of MC4R complexes simulating a presumably active-state conformation compared to the structure of the inactive state, we here briefly summarize the current understanding and key players involved in the MC4R switching process between different activity states. Finally, these perspectives highlight the complexity and plasticity in MC4R signaling regulation and identify gaps in our current knowledge.
Highlights
The G protein-coupled receptor (GPCR)-linked modular and plastic signaling system is one of the main signaling pathways in eukaryotes and evolved early in eukaryotic evolution [1,2]
Over 300 GPCR structures from more than 70 unique receptors were determined by protein X-ray crystallography or by cryo-electron microscopy, including different conformations or substates and receptor complexes with G proteins, arrestins, or peptides derived from both, respectively [18,19,20]
Agonist action (e.g., by α-melanocyte-stimulating hormone (α-MSH)) in the melanocortin-4 receptor (MC4R) induces an appetite-reducing effect [34], in contrast to the inverse agonist ligand agouti-related peptide (AgRP) with appetite-enhancing effect [35,36]. This endogenous counter-regulation mechanism at the ligand level is of specific interest, since other endogenous inverse agonists have not been described for GPCRs so far, with the exception of agouti-signaling protein for the MC1R [24] and the inverse agonistic molecule retinal permanently bound in rhodopsin [37]
Summary
The G protein-coupled receptor (GPCR)-linked modular and plastic signaling system is one of the main signaling pathways in eukaryotes and evolved early in eukaryotic evolution [1,2]. Agonist action (e.g., by α-melanocyte-stimulating hormone (α-MSH)) in the MC4R induces an appetite-reducing effect [34], in contrast to the inverse agonist ligand agouti-related peptide (AgRP) with appetite-enhancing effect [35,36] This endogenous counter-regulation mechanism at the ligand level is of specific interest, since other endogenous inverse agonists have not been described for GPCRs so far, with the exception of agouti-signaling protein for the MC1R [24] and the inverse agonistic molecule retinal permanently bound in rhodopsin [37]. In agreement with other GPCR examples, this supports a fundamental role of the EL2 for MC4R function, in particular for peptide ligand binding It remains unknown whether this interaction between the EL2 and the antagonist SHU9119 is relevant for agonistic ligand binding; it should be important for the distinction between agonistic and antagonistic ligand action. Of special interest is the observation of orthosteric vs. allosteric binding of these small-molecule ligands to MC4R of different species [26,114,131]; the molecular basis of this differential binding and signaling effect remains to be investigated
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