Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective

Heyder, Nicolas A.; Kleinau, Gunnar; Szczepek, Michal; Kwiatkowski, Dennis; Speck, David; Soletto, Lucía; Cerdá‐Reverter, José Miguel; Krude, Heiko; Kühnen, Peter; Biebermann, Heike; Scheerer, Patrick

doi:10.3389/fendo.2019.00515

Cited by 29 publications

(33 citation statements)

References 149 publications

(225 reference statements)

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“…The confirmed mRNA sequences of the qPCR amplicons indicated that all four salmon mc4r genes are not pseudogenes. The Atlantic salmon showed wellconserved seven hydrophobic transmembrane domains as well as one putative disulfide bond, within the ECL3 for Mc4ra1 (Cys274 and Cys280) and Mc4rb2 (Cys275 and Cys281), as described for human MC4R (Cys271 and Cys277) (Chai et al, 2005;Chapman et al, 2010;Heyder et al, 2019). Even though Cys are also present in the primary sequence of Mc4ra2 and Mc4rb1, a disulfide bond was not present in the predicted tertiary structure in PyMOL.…”

Section: Discussionmentioning

confidence: 93%

“…In general, for human MC4Rs, the pocket of aspartic acid Asp122/126 in TMHIII and basic histidine (His) 264 residues in TMHVI (Metz et al, 2006;Chapman et al, 2010;Wen et al, 2017;Heyder et al, 2019) along with ECL2 and ECL3 (Tao, 2010) are essential for ligand binding. β-MSH has been shown to the have the highest affinity to human MC4R, followed by α-MSH and ACTH (Tao, 2010).…”

Section: Discussionmentioning

confidence: 99%

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The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control

et al. 2020

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The melanocortin system is a key neuroendocrine network involved in the control of food intake and energy homeostasis in vertebrates. Within the hypothalamus, the system comprises two main distinct neuronal cell populations that express the neuropeptides proopiomelanocortin (POMC; anorexigenic) or agouti-related protein (AGRP; orexigenic). Both bind to the melanocortin-4 receptor (MC4R) in higher order neurons that control both food intake and energy expenditure. This system is relatively well-conserved among vertebrates. However, in Atlantic salmon (Salmo salar L.), the salmonid-specific fourth round whole-genome duplication led to the presence of several paralog genes which might result in divergent functions of the duplicated genes. In the current study, we report the first comprehensive comparative identification and characterization of Mc4r and extend the knowledge of Pomc and Agrp in appetite control in Atlantic salmon. In silico analysis revealed multiple paralogs for mc4r (a1, a2, b1, and b2) in the Atlantic salmon genome and confirmed the paralogs previously described for pomc (a1, a2, and b) and agrp (1 and 2). All Mc4r paralogs are relatively well-conserved with the human homolog, sharing at least 63% amino acid sequence identity. We analyzed the mRNA expression of mc4r, pomc, and agrp genes in eight brain regions of Atlantic salmon post-smolt under two feeding states: normally fed and fasted for 4 days. The mc4ra2 and b1 mRNAs were predominantly and equally abundant in the hypothalamus and telencephalon, the mc4rb2 in the hypothalamus, and a1 in the telencephalon. All pomc genes were highly expressed in the pituitary, followed by the hypothalamus and saccus vasculosus. The agrp genes showed a completely different expression pattern from each other, with prevalent expression of the agrp1 in the hypothalamus and agrp2 in the telencephalon. Fasting did not induce any significant changes in the mRNA level of mc4r, agrp, or pomc paralogs in the hypothalamus or in other highly expressed regions between fed and fasted states. The identification and wide distribution of multiple paralogs of mc4r, pomc, and agrp in Atlantic salmon brain provide new insights and give rise to new questions of the melanocortin system in the appetite regulation in Atlantic salmon.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control

et al. 2020

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“…This hints to the importance of the G q/11 pathway, as a strong bias towards PLC activation of V103I might play a part in its suggested protective role against obesity [30][31][32][33][34]. The rare mutation H158R is located in the ICL2, which is part of the G protein binding site and has been postulated to be important for G q/11 coupling as well [64]. The observed gain-of-function in this pathway therefore suggests functional relevance of this position.…”

Section: Signaling Bias Towards G Q/11 Of Two Mutations When Stimulatmentioning

confidence: 85%

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

Paisdzior

Dimitriou

Schöpe

et al. 2020

IJMS

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The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.

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“…In contrast to most of the other class A GPCRs, the MC4R EL2 has been reported to only consist of three to four amino acids (e.g., [ 48 ]), which has been recently confirmed by the inactive MC4R crystal structure [ 21 ] ( Figure 2 and Figure 4 ). Usually, in class A GPCRs, the EL2 comprises ~10–30 amino acids and is located centrally above the transmembrane helical bundle.…”

Section: Specific Features In the Mc4r Sequence And Structure Linkmentioning

confidence: 87%

“…This is also of importance because obesity is related to different comorbidities, such as type 2 diabetes mellitus or cardiovascular disease [ 47 ]. To date, approximately 165 missense mutations in 129 different residues have been reported [ 48 ]. Several of these pathogenic MC4R mutations have been observed to cause biased signaling through the MC4R by forcing preference for a specific signaling pathway [ 39 , 49 , 50 , 51 , 52 ] (reviewed in [ 35 ]).…”

Section: The Melanocortin-4 Receptormentioning

confidence: 99%

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

Kleinau

Heyder

Tao

et al. 2020

IJMS

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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.

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Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective

Cited by 29 publications

References 149 publications

The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control

The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

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

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