Pharmacological modulation of dual melanocortin‐4 receptor signaling by melanocortin receptor accessory proteins in the Xenopus laevis

2021 ◽  
Author(s):  
Lei Li ◽  
Ying Xu ◽  
Jihong Zheng ◽  
Zhe Kuang ◽  
Cong Zhang ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Melanocortin Receptor ◽  
Accessory Proteins ◽  
Receptor Signaling ◽  
Pharmacological Modulation ◽  
Melanocortin 4 Receptor

scholarly journals Pharmacological modulation of the cAMP signaling of two isoforms of melanocortin-3 receptor by melanocortin receptor accessory proteins in the tetrapod Xenopus laevis

2021 ◽  
Author(s):  
Ying Xu ◽  
Lei Li ◽  
Jihong Zheng ◽  
Meng Wang ◽  
Bopei Jiang ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Energy Homeostasis ◽  
Surface Expression ◽  
Immunofluorescence Assay ◽  
Melanocortin Receptor ◽  
Accessory Proteins ◽  
Melanocortin System ◽  
Pharmacological Modulation ◽  
In Vitro Interaction

As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals and its pharmacological effect could be directly influenced by the presence of melanocortin accessory proteins, MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not been thoroughly evaluated yet. In this work, we performed sequence alignment, phylogenetic and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.

The role of accessory proteins in melanocortin receptor signaling

2008 ◽  
Vol 13 (9) ◽  
pp. 569-569
Author(s):  
G. Barsh ◽  
S. Candille ◽  
L. He ◽  
S. Aradhya ◽  
J. Kerns
Keyword(s):  
Melanocortin Receptor ◽  
Accessory Proteins ◽  
Receptor Signaling

scholarly journals Melanocortin Receptor Accessory Protein 2-Induced Adrenocorticotropic Hormone Response of Human Melanocortin 4 Receptor

2018 ◽  
Vol 3 (2) ◽  
pp. 314-323 ◽  
Author(s):  
Lucia Soletto ◽  
Sergio Hernández-Balfagó ◽  
Ana Rocha ◽  
Patrick Scheerer ◽  
Gunnar Kleinau ◽  
...  
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Hormone Response ◽  
Melanocortin 4 Receptor ◽  
Receptor Accessory Protein

A Novel Loss of Function Melanocortin-4-Receptor Mutation (MC4R-F313Sfs*29) in Morbid Obesity

2020 ◽  
Author(s):  
Elisabetta Trevellin ◽  
Marnie Granzotto ◽  
Cristina Host ◽  
Francesca Grisan ◽  
Diego De Stefani ◽  
...  
Keyword(s):  
Early Onset ◽  
Functional Characterization ◽  
Gene Mutations ◽  
Melanocortin Receptor ◽  
Hek293 Cells ◽  
Intracellular Camp ◽  
Loss Of Function ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor

Abstract Context Melanocortin receptor-4 (MC4R) gene mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. Objective To explore whether and how a novel heterozygous MC4R variant (MC4R-F313Sfs*29), identified in a young boy (body mass index [BMI] 38.8 kg/m2) during a mutation analysis conducted in a cohort of patients with obesity, plays a determinant pathophysiological role in the obesity development. Design Setting and Patients The genetic screening was carried out in a total of 209 unrelated patients with obesity (BMI ≥ 35 kg/m2). Structural and functional characterization of the F313Sfs*29-mutated MC4R was performed using computational approaches and in vitro, using HEK293 cells transfected with genetically encoded biosensors for cAMP and Ca2+. Results The F313Sfs*29 was the only variant identified. In vitro experiments showed that HEK293 cells transfected with the mutated form of MC4R did not increase intracellular cAMP or Ca2+ levels after stimulation with a specific agonist in comparison with HEK293 cells transfected with the wild type form of MC4R (∆R/R0 = -90% ± 8%; P < 0.001). In silico modeling showed that the F313Sfs*29 mutation causes a major reorganization in the cytosolic domain of MC4R, thus reducing the affinity of the putative GalphaS binding site. Conclusions The newly discovered F313Sfs*29 variant of MC4R may be involved in the impairment of α-MSH-induced cAMP and Ca2+ signaling, blunting intracellular G protein-mediated signal transduction. This alteration might have led to the dysregulation of satiety signaling, resulting in hyperphagia and early onset of obesity.

scholarly journals Melanocortin 4 receptor signaling in dopamine 1 receptor neurons is required for procedural memory learning

2012 ◽  
Vol 106 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Huxing Cui ◽  
Brittany L. Mason ◽  
Charlotte Lee ◽  
Akinori Nishi ◽  
Joel K. Elmquist ◽  
...  
Keyword(s):  
Procedural Memory ◽  
Receptor Signaling ◽  
Melanocortin 4 Receptor ◽  
Receptor Neurons

Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced fever in rats

2003 ◽  
Vol 284 (6) ◽  
pp. R1595-R1603 ◽  
Author(s):  
Partha S. Sinha ◽  
Helgi B. Schiöth ◽  
Jeffrey B. Tatro
Keyword(s):  
Systemic Treatment ◽  
Core Body Temperature ◽  
Melanocortin Receptor ◽  
Melanocortin Receptors ◽  
Antipyretic Effect ◽  
Selective Agonist ◽  
Melanocortin 4 Receptor ◽  
Heat Conservation ◽  
Core Body ◽  
Escherichia Coli Lipopolysaccharide

Activation of central melanocortin receptors (MCR) inhibits fever, but the identity of the MCR subtype(s) mediating this antipyretic effect is unknown. To determine whether selective central melanocortin receptor-4 (MC4R) activation produces antipyretic effects, the MC4R selective agonist MRLOB-0001 (CO-His-d-Phe-Arg-Trp-Dab-NH2) was administered intracerebroventricularly to rats treated with Escherichia coli lipopolysaccharide (LPS, 30 μg/kg ip). Treatment with MRLOB-0001 (150 ng icv) did not lower core body temperature (Tc) in afebrile rats but did suppress LPS-induced increases in Tc and associated decreases in tail skin temperature (Tsk), an indicator of vasomotor thermoeffector function. In contrast, systemic treatment with MRLOB-0001 (150 ng iv) did not produce similar antipyretic effects. Coadministration of the selective MC4R antagonist HS014 (1 μg icv) blocked the antipyretic effects of MRLOB-0001. HS014 alone (1 μg icv) had no significant effect on LPS-induced increases in Tc or decreases in Tsk and in afebrile rats had no significant effects on Tc or Tsk. We conclude that pharmacological activation of central MC4R suppresses febrile increases in Tc and that inhibition of heat conservation pathways may contribute to this effect. These findings suggest that the central MC4R may mediate the long-recognized antipyretic effects of centrally administered melanocortins.

scholarly journals Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways

2007 ◽  
Vol 6 (5) ◽  
pp. 398-405 ◽  
Author(s):  
Ligang Zhou ◽  
Gregory M. Sutton ◽  
Justin J. Rochford ◽  
Robert K. Semple ◽  
Daniel D. Lam ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Signaling Pathways ◽  
Receptor Signaling ◽  
Serotonin 2C Receptor ◽  
Receptor Agonists ◽  
Melanocortin 4 Receptor
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