MRAP2 Interaction with Melanocortin-4 Receptor in SnakeHead (Channa argus)

Wen, Zhengyong; Liu, Ting; Qin, Chuanjie; Zou, Youlan; Wang, Jun; Li, Rui; Tao, Ya‐Xiong

doi:10.3390/biom11030481

Cited by 28 publications

(28 citation statements)

References 66 publications

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“…For instance, the surface expression of clawed frog MC3R was suppressed by MRAP2 (45), whereas in our study, axolotl MRAP2 did not affect the cell surface expression of MC3R. MRAP2 showed no effect on cell surface expression of MC4R in both chicken (43) and snakehead (49). However, MRAP2 could significantly decrease the surface level of MC4R in tilapia (70).…”

Section: Discussioncontrasting

confidence: 77%

“…Several studies have been conducted to evaluate the pharmacological profiles of MC3R/MC4R in the presence of MRAPs in various vertebrates, such as human ( 40 , 41 ), mouse ( 42 ), chicken ( 43 ), the clawed frog ( 44 – 46 ), zebrafish ( 47 , 48 ), snakehead ( 49 ), orange-spotted grouper ( 50 ), channel catfish ( 51 ), topmouth culter ( 52 , 53 ), and sea lamprey ( 54 ). For instance, human MRAP2 was found to promote the maximal activity of MC3R/MC4R stimulated by α-MSH, whereas the mutated MRAP2 variants failed to show the similar effect ( 40 ).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Evaluation of Melanocortin 2 Receptor Accessory Protein 2 on Axolotl Neural Melanocortin Signaling

et al. 2022

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The Melanocortin-3 receptor (MC3R) and Melanocortin-4 receptor (MC4R), two members of the key hypothalamic neuropeptide signaling, function as complex mediators to control the central appetitive and energy homeostasis. The melanocortin 2 receptor accessory protein 2 (MRAP2) is well-known for its modulation on the trafficking and signaling of MC3R and MC4R in mammals. In this study, we cloned and elucidated the pharmacological profiles of MRAP2 on the regulation of central melanocortin signaling in a relatively primitive poikilotherm amphibian species, the Mexican axolotl (Ambystoma mexicanum). Our results showed the higher conservation of axolotl mc3r and mc4r across species than mrap2, especially the transmembrane regions in these proteins. Phylogenetic analysis indicated that the axolotl MC3R/MC4R clustered closer to their counterparts in the clawed frog, whereas MRAP2 fell in between the reptile and amphibian clade. We also identified a clear co-expression of mc3r, mc4r, and mrap2 along with pomc and agrp in the axolotl brain tissue. In the presence of MRAP2, the pharmacological stimulation of MC3R by α-MSH or ACTH significantly decreased. MRAP2 significantly decreased the cell surface expression of MC4R in a dose dependent manner. The co-localization and formation of the functional complex of axolotl MC3R/MC4R and MRAP2 on the plasma membrane were further confirmed in vitro. Dramatic changes of the expression levels of mc3r, mrap2, pomc, and agrp in the fasting axolotl hypothalamus indicated their critical roles in the metabolic regulation of feeding behavior and energy homeostasis in the poikilotherm aquatic amphibian.

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Section: Discussioncontrasting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Pharmacological Evaluation of Melanocortin 2 Receptor Accessory Protein 2 on Axolotl Neural Melanocortin Signaling

et al. 2022

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“…Only three studies have investigated the pharmacological properties of fish MC3Rs so far (43,44,49). Of interest, two studies reported high constitutive activities in zebrafish and channel catfish MC3Rs (43,49), similar to the results in teleost MC4Rs (39,40,41,47,50,51,52,53) and MC1R (54). In this study, topmouth culter (Culter alburnus) was used as an animal model to explore physiology and pharmacology of culter MC3R.…”

Section: Introductionmentioning

confidence: 71%

“…Targeted deletion of Mrap2 in mice shows severe obesity ( 36 , 37 ). MRAP2 interacts with and modulates MC4R signaling in mammals and other species ( 33 , 38 , 39 , 40 , 41 , 42 ). Additionally, the function of MRAP2 in regulating energy homeostasis through MC3R has also been reported ( 32 , 38 , 43 ).…”

Section: Introductionmentioning

confidence: 99%

Topmouth culter melanocortin-3 receptor: regulation by two isoforms of melanocortin-2 receptor accessory protein 2

Huang

Wang

et al. 2021

Endocrine Connections

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Melanocortin-3 receptor (MC3R) is a regulator of energy homeostasis, and interaction of MC3R and melanocortin-2 receptor accessory protein 2 (MRAP2) plays a critical role in MC3R signaling of mammals. However, the physiological roles of MC3R in teleosts are not well understood. In this study, qRT-PCR was used to measure gene expression. Radioligand binding assay was used to study the binding properties of topmouth culter MC3R (caMC3R). Intracellular cAMP generation was determined by radioimmunoassay and caMC3R expression was quantified with flow cytometry. We showed that culter mc3r had higher expression in the central nervous system. All agonists could bind and stimulate caMC3R to increase dose-dependently intracellular cAMP accumulation. Compared to hMC3R, culter MC3R showed higher constitutive activity, higher efficacies and Rmax to α-MSH, des-α-MSH, and ACTH. Both caMRAP2a and caMRAP2b markedly decreased caMC3R basal cAMP production. However, only caMRAP2a significantly decreased cell surface expression, Bmax and Rmax of caMC3R. Expression analysis suggested that MRAP2a and MRAP2b might be more important in regulating MC3R/MC4R signaling during larval period, and reduced mc3r, mc4r, and pomc expression might be primarily involved in modulation of MC3R/MC4R in adults. These data indicated that the cloned caMC3R was a functional receptor. MRAP2a and MRAP2a had different effects on expression and signaling of caMC3R. In addition, expression analysis suggested that MRAP2s, receptors, and hormone might play different roles in regulating culter development and growth.

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“…Previous studies found that MC4R could form homodimer [ 30 ] and interacted with attractin-like protein (ALP) in mice [ 31 ]. In addition, MC4R signaling could be regulated in various species by interactions with MRAP and MRAP2, including alterations of ligand affinity and surface expression [ [32] , [33] , [34] , [35] , [36] , [37] ]. MC3R was able to interact with ghrelin receptor (GHSR) and the enhanced melanocortin-induced intracellular cAMP accumulation [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel GPCR partners of the central melanocortin signaling

Liu

Wang

et al. 2021

Molecular Metabolism

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Objective Homo- or heterodimerization of G protein–coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo . It is well known that melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are key regulators of appetite and energy homeostasis in the central nervous system (CNS). However, the GPCR partners of MC3R and MC4R are not well understood. Our objective is to analyze single cell RNA-seq datasets of the hypothalamus to explore and identify novel GPCR partners of MC3R and MC4R and examine the pharmacological effect on the downstream signal transduction and membrane translocation of melanocortin receptors. Methods We conducted an integrative analysis of multiple single cell RNA-seq datasets to reveal the expression pattern and correlation of GPCR families in the mouse hypothalamus. The emerging GPCRs with important metabolic functions were selected for cloning and co-immunoprecipitation validation. The positive GPCR partners were then tested for the pharmacological activation, competitive binding assay and surface translocation ELISA experiments. Results Based on the expression pattern of GPCRs and their function enrichment results, we narrowed down the range of potential GPCR interaction with MC3R and MC4R for further confirmation. Co-immunoprecipitation assay verified 23 and 32 novel GPCR partners that interacted with MC3R and MC4R in vitro . The presence of these GPCR partners exhibited different effects in the physiological regulation and signal transduction of MC3R and MC4R. Conclusions This work represented the first large-scale screen for the functional GPCR complex of central melanocortin receptors and defined a composite metabolic regulatory GPCR network of the hypothalamic nucleuses.

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MRAP2 Interaction with Melanocortin-4 Receptor in SnakeHead (Channa argus)

Cited by 28 publications

References 66 publications

Pharmacological Evaluation of Melanocortin 2 Receptor Accessory Protein 2 on Axolotl Neural Melanocortin Signaling

Pharmacological Evaluation of Melanocortin 2 Receptor Accessory Protein 2 on Axolotl Neural Melanocortin Signaling

Topmouth culter melanocortin-3 receptor: regulation by two isoforms of melanocortin-2 receptor accessory protein 2

Identification of novel GPCR partners of the central melanocortin signaling

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