Pharmacological modulation of two melanocortin-5 receptors by MRAP2 proteins in zebrafish

Zhu, Ming; Wang, Meng; Chen, Yijun; Zhang, Chao

doi:10.1530/jme-18-0104

Cited by 13 publications

(14 citation statements)

References 26 publications

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“…MRAPs and MCRs have been reported to form homodimers in vitro (10, 27, 28, 29, 30). Our recent work demonstrated that zebrafish MC5Ra and MC5Rb could form homo- and heterodimers, which could be disrupted by MRAP2a or MRAP2b proteins (24). Therefore, we also conducted YFP luminescent assays and identified the formation of antiparallel homodimers of slMRAP2.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological modulation of MRAP2 protein on melanocortin receptors in the sea lamprey

Zhu

Wang

et al. 2019

Endocrine Connections

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Melanocortin receptors (MCRs) and their accessory proteins (MRAPs) evolutionarily first appear in the genome of sea lamprey. The most ancient melanocortin system consists of only two melanocortin receptors (slMCa and slMCb) and one MRAP2 (slMRAP2) protein, but the physiological roles have not been fully explored in this primitive species. Here, we synthesize and characterize the pharmacological features of slMRAP2 protein on two slMCRs. Our results show that the slMRAP2 protein lacks the long carboxyl terminus; it directly interacts and decreases the surface expression but enhances the α-MSH-induced agonism of slMCa and slMCb. In comparison with higher organisms such as elephant shark and zebrafish, we also demonstrate the constantly evolving regulatory function of the carboxyl terminus of MRAP2 protein, the unique antiparallel topology of slMRAP2 dimer and the homo- and hetero-dimerization of two slMCRs. This study elucidates the presence and modulation of melanocortin receptor by the accessory protein of the agnathans for the first time, which provides a better insight of the melanocortin system in ancient species of chordates.

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Section: Discussionmentioning

confidence: 99%

“…Cells were then treated with a fixed concentration of α-MSH (2 nM) and different concentrations of AgRP in DMEM supplemented with 0.1% bovine serum albumin for 4 h at 37°C. The cAMP level was measured as described before (24) using the Dual-Glo Luciferase Assay System (Promega). Luminescence was measured with a Spectramax M5 plate reader.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological modulation of MRAP2 protein on melanocortin receptors in the sea lamprey

Zhu

Wang

et al. 2019

Endocrine Connections

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“…In such cases, the respective contributions of monomers and dimers to the cellular signaling output are usually unclear, which hinders appropriate interpretation of, e.g., dose-response curves in terms of a dissection between monomer/oligomer mediated signaling. The potential functional relevance of oligomeric constellations is also confirmed for the zfMC5R, whereby receptor oligomerization is hindered by the protein interaction with zebrafish Mrap2 (114).…”

Section: Resultsmentioning

confidence: 80%

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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“…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 ]. Here, we transfected HEK293T cells with 3HA-SRIF1s and 2Flag-MRAP1/2 to determine whether MRAP1/MRAP2 could interact with SSTRs.…”

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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Pharmacological modulation of two melanocortin-5 receptors by MRAP2 proteins in zebrafish

Cited by 13 publications

References 26 publications

Pharmacological modulation of MRAP2 protein on melanocortin receptors in the sea lamprey

Pharmacological modulation of MRAP2 protein on melanocortin receptors in the sea lamprey

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

Selective Interactions of Mouse Melanocortin Receptor Accessory Proteins with Somatostatin Receptors

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