Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Sharma, Shubh D.; Garfield, Alastair S.; Shah, Bhavik P.; Kleyn, Patrick; Ichetovkin, Ilia; Moeller, Ida; Mowrey, William R.; Ploeg, Lex H.T. Van der

doi:10.3390/molecules24101892

Cited by 40 publications

(33 citation statements)

References 48 publications

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“…Interestingly, a previous study reported that zfMC4R shows increased ACTH sensitivity mediated by the escort protein MRAP2a (93). Similar results with MRAP2 were reported recently for chicken (60) and for the human MC4R (71). Only MC2R has been known to usually interact with ACTH with high affinity.…”

Section: Resultssupporting

confidence: 91%

“…This can be reasoned by the identification of two MRAP paralogue genes in zebrafish, zfMRAP2a, and zfMRAP2b (69), with zfMRAP2a found to increase the zfMC4R response to ACTH, most likely by heteromerization [Josep et al (70)]. Consequently, zfMC4R becomes an ACTH receptor in the presence of MRAP2a and similar results have been reported recently in chickens (60) and also for the human MC4R (71) in interaction with MRAP2. Therefore, our complex models should help to generate functional mechanistic hypotheses concerning increased ACTH sensitivity at zfMC4R mediated by interaction with MRAP2a, although we cannot offer a concrete heteromeric MC4R/MRAP2 complex model because of missing structural information on MRAP (no valuable template or elucidated structure is available).…”

Section: Methodssupporting

confidence: 59%

“…While many MCR ligands, synthetic or endogenous, are already known (59, 60), we here focused only on a small subset of endogenous native ligands such as alpha-MSH or AgRP to link structural models with the different aspects of MC4R signaling and regulation. We recently described a modeling and docking procedure for the hMC4R in a complex with the agonistic peptide ligands α-MSH and setmelanotide (50).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating MC4R variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of inter alia non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for the MC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.

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Section: Resultssupporting

confidence: 91%

Section: Methodssupporting

confidence: 59%

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…Of the five MCRs, MC2R is only activated by ACTH, whereas the other four MCRs can be activated by both α- and β-MSHs, and γ-MSH preferentially binds to the MC3R [ 25 , 163 , 164 , 165 , 166 ]. Of the two endogenous antagonists, agouti antagonizes MC1R, although when expressed ubiquitously, it can also antagonize MC4R [ 167 ].…”

Section: Specific Features In the Mc4r Sequence And Structure Linkmentioning

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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“…It has been shown to suppress food intake and body weight in obese mice and monkeys ( Collet et al., 2017 ), and clinical treatment on three severely obese LEPR -deficient individuals shows substantial and durable reductions in hyperphagia and body weight over 45‒61 weeks ( Clement et al., 2018 ). Currently, setmelanotide is in the phase 3 clinical trial for various human obesity syndromes, including POMC deficiency, LEPR deficiency, Bardet–Biedl syndrome, Alström syndrome, and others with impaired MC4R pathway ( Kuhnen et al., 2019 ; Sharma et al., 2019 ).…”

Section: Genetic Variants Affecting the Central Melanocortin System Cmentioning

confidence: 99%

The central melanocortin system and human obesity

Yang

2020

Journal of Molecular Cell Biology

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The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.

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Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Cited by 40 publications

References 48 publications

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

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

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

The central melanocortin system and human obesity

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