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

Xu, Ying; Li, Lei; Zheng, Jihong; Wang, Meng; Jiang, Bopei; Zhai, Yue; Lu, Liumei; Zhang, Cong; Kuang, Zhe; Yang, Xiaomei; Jin, Lihua; Lin, Gufa; Zhang, Chao

doi:10.1530/ec-21-0179

Cited by 6 publications

(8 citation statements)

References 40 publications

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“…The MRAP family (MRAP1 and MRAP2) were originally identified to modulate the signaling and dimerization of the melanocortin receptor family in several species [ 29 , 30 , 31 , 32 , 33 , 34 ]. Recently, they were also found to regulate the trafficking and activity of several other non-melanocortin GPCRs (such as PKR1, OX1R and GHSR1a) [ 34 , 35 , 36 , 37 , 38 , 39 ].…”

Section: Resultsmentioning

confidence: 99%

Selective Interactions of Mouse Melanocortin Receptor Accessory Proteins with Somatostatin Receptors

Wang

Lei

et al. 2022

Cells

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Somatostatin receptors (SSTRs) are G protein-coupled receptors (GPCRs) known to regulate exocrine secretion, neurotransmission, and inhibit endogenous cell proliferation. SSTR subtypes (SSTR1-SSTR5) exhibit homo- or heterodimerization with unique signaling characteristics. Melanocortin receptor accessory protein 1 (MRAP1) functions as an allosteric modulator of melanocortin receptors and some other GPCRs. In this study, we investigated the differential interaction of MRAP1 and SSTRs and examined the pharmacological modulation of MRAP1 on mouse SSTR2/SSTR3 and SSTR2/SSTR5 heterodimerization in vitro. Our results show that the mouse SSTR2 forms heterodimers with SSTR3 and SSTR5 and that MRAP1 selectively interacts with SSTR3 and SSTR5 but not SSTR2. The interactive binding sites of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 locate on SSTR3 and SSTR5 but not SSTR2. The binding sites of MRAP1 to SSTR3 are extensive, while the ones of SSTR5 are restricted on transmembrane region six and seven. The heterodimerization of mouse SSTR2, SSTR3, and SSTR5 can be modulated by binding protein in addition to an agonist. Upregulation of extracellular signal-regulated kinases phosphorylation, p27Kip1, and increased cell growth inhibition with the co-expression of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 suggest a regulatory effect of MRAP1 on anti-proliferative response of two SSTR heterodimers. Taken together, these results provide a new insight of MRAP1 on the maintenance and regulation of mouse SSTR dimers which might be helpful to better understand the molecular mechanism involving SSTRs in tumor biology or other human disorders.

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Section: Resultsmentioning

confidence: 99%

Selective Interactions of Mouse Melanocortin Receptor Accessory Proteins with Somatostatin Receptors

Wang

Lei

et al. 2022

Cells

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“…In addition to high expression level of human brain, MRAP2 shows a broader distribution among other human tissues than MC3R / MC4R , indicating that its function might not limit to the energy homeostasis. In the clawed frog, mc3r and mc4r are expressed in brain region with low abundance in some peripheral tissues, whereas mrap2 distributes widely among multiple tissues including brain ( 45 , 46 ). Moreover, in the zebrafish only mrap2a expressed in larval zebrafish, while mrap2b expression emerged until the adult stage, suggesting that these two genes could participate in the metabolic regulation at different life stages ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, MRAPs were identified to improve the MC4R ligand sensitivity to ACTH in chicken (43). Similarly, MRAPs were reported to mediate the pharmacological activities of the neuronal MC3R and MC4R signaling in clawed frog (44)(45)(46) and sea lamprey (54). Therefore, the interaction and regulation of the melanocortin signaling in other vertebrates remain unclear and intriguing.…”

Section: Introductionmentioning

confidence: 99%

“…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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“…As a paralogue of MRAP, MRAP2 shares a conserved functional domain and similar structural features with MRAP. However, unlike MRAP, which mainly regulates MC2R in the adrenal gland, MRAP2 shows more preference for the other four MCRs [ 16 , 17 , 18 , 19 , 20 ], as well as several non-melanocortin receptors, such as orexin receptor and ghrelin receptor [ 21 , 22 , 23 , 24 , 25 ]. MRAP2 is involved in energy balance and metabolism by regulating MC4R activity in many organisms [ 18 , 20 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Reversion of MRAP2 Protein Sequence Generates a Functional Novel Pharmacological Modulator for MC4R Signaling

Wang

et al. 2022

Biology

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As a member of the melanocortin receptor family, melanocortin 4 receptor (MC4R) plays a critical role in regulating energy homeostasis and feeding behavior, and has been proven as a promising therapeutic target for treating severe obesity syndrome. Numerous studies have demonstrated that central MC4R signaling is significantly affected by melanocortin receptor accessory protein 2 (MRAP2) in humans, mice and zebrafish. MRAP2 proteins exist as parallel or antiparallel dimers on the plasma membrane, but the structural insight of dual orientations with the pharmacological profiles has not yet been fully studied. Investigation and optimization of the conformational topology of MRAP2 are critical for the development of transmembrane allosteric modulators to treat MC4R-associated disorders. In this study, we synthesized a brand new single transmembrane protein by reversing wild-type mouse and zebrafish MRAP2 sequences and examined their dimerization, interaction and pharmacological activities on mouse and zebrafish MC4R signaling. We showed that the reversed zebrafish MRAPa exhibited an opposite function on modulating zMC4R signaling and the reversed mouse MRAP2 lost the capability for regulating MC4R trafficking but exhibited a novel function for cAMP cascades, despite proper expression and folding. Taken together, our results provided new biochemical insights on the oligomeric states and membrane orientations of MRAP2 proteins, as well as its pharmacological assistance for modulating MC4R signaling.

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

Cited by 6 publications

References 40 publications

Selective Interactions of Mouse Melanocortin Receptor Accessory Proteins with Somatostatin Receptors

Selective Interactions of Mouse Melanocortin Receptor Accessory Proteins with Somatostatin Receptors

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

Reversion of MRAP2 Protein Sequence Generates a Functional Novel Pharmacological Modulator for MC4R Signaling

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