Structural Complexity and Plasticity of Signaling Regulation at the Melanocortin-4 Receptor

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.

Zebrafish Bioassay for Screening Therapeutic Candidates Based on Melanotrophic Activity

“…This is in agreement with recent insights from a human MC1R/α-MSH complex [25]. In addition, we assume that any variation in this position does not alter the ligand structure itself, as in high-affinity MSH subtypes (e.g., β-MSH) this position is also variable [26] as observed here in α-MSH variants of different species (Figure 2b). These findings and predictions are consistent with the results of our in vivo assay, which demonstrates the biological activity of the tested ligands, albeit with varying degrees of melanosome dispersion; however, we cannot rule out that amino acid variations could cause a slight change in receptor binding (e.g., with the N-terminus not included in determined structures or in the half-life of the synthetic peptides).…”

Melanocortin Receptor 4 (MC4R) Signaling System in Nile Tilapia

“…In mammals and birds, this signaling system consists of MC4R (a G protein-coupled receptor), MC4R ligands [α-melanocyte-stimulating hormone (α-MSH); adrenocorticotropin (ACTH), and agouti-related peptide (AgRP)], and melanocortin receptor 2 accessary protein 2 (MRAP2) [ 2 , 5 ]. α-MSH and ACTH are derived from the proopiomelanocortin (POMC) precursor and can activate MC4R and increase intracellular cAMP levels, while AgRP can act either as an antagonist to block α-MSH/ACTH action on MC4R, or as an inverse agonist to decrease the basal constitutive activity of MC4R in the absence of α-MSH/ACTH [ 1 , 7 , 8 ]. MRAP2 is a single-pass transmembrane protein and can form an antiparallel homodimer [ 9 ].…”

A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation

“…In a dimeric state, only one G protein molecule can access the receptor dimer, due to steric reasons (stoichiometry 2:1). A monomerized receptor is able to couple one G protein molecule to each receptor (stoichiometry 2:2); this might cause higher signaling capacities due to doubled G protein activation [ 42 ]. This mechanism is important when wanting to discuss possibilities for therapeutical interventions.…”