Determination of the Interaction and Pharmacological Modulation of MCHR1 Signaling by the C-Terminus of MRAP2 Protein

Wang, Meng; Zhai, Yue; Lei, Xiaowei; Xu, Jing; Jiang, Bopei; Kuang, Zhe; Zhang, Cong; Liu, Shangyun; Bian, Shan; Yang, Xiaomei; Zan, Tao; Jin, Lihua; Li, Qingfeng

doi:10.3389/fendo.2022.848728

Cited by 5 publications

(3 citation statements)

References 27 publications

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“…MRAP2 prevents ghrelin‐stimulated GHSR1a phosphorylation to alter GHSR1a signaling and inhibit the recruitment of β ‐arrestin. [ 124 ] In addition, MRAP2 protein interacts with melanin‐concentrating hormone receptor 1 (MCHR1) to regulate appetite and energy homeostasis [ 125 ] and also selectively interacts with the growth inhibitory hormone receptor (SSTR) to regulate exocrine secretion, inhibit endogenous cell proliferation, etc. [ 126 ]…”

Section: The Mc4r Signaling Pathwaymentioning

confidence: 99%

MC4R in Central and Peripheral Systems

Wei

Jia

et al. 2023

Advanced Biology

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Obesity has emerged as a critical and urgent health burden during the current global pandemic. Among multiple genetic causes, melanocortin receptor‐4 (MC4R), involved in food intake and energy metabolism regulation through various signaling pathways, has been reported to be the lead genetic factor in severe and early onset obesity and hyperphagia disorders. Most previous studies have illustrated the roles of MC4R signaling in energy intake versus expenditure in the central system, while some evidence indicates that MC4R is also expressed in peripheral systems, such as the gut and endocrine organs. However, its physiopathological function remains poorly defined. This review aims to depict the central and peripheral roles of MC4R in energy metabolism and endocrine hormone homeostasis, the diversity of phenotypes, biased downstream signaling caused by distinct MC4R mutations, and current drug development targeting the receptor.

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Section: The Mc4r Signaling Pathwaymentioning

confidence: 99%

MC4R in Central and Peripheral Systems

Wei

Jia

et al. 2023

Advanced Biology

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“…Therefore, whether the MRAP family could regulate other GPCR signaling attracted much attention for all melanocortin communities. A few evidence have shown that MRAP proteins could regulate the signaling and activity of additional non-melanocortin GPCRs, such as orexin receptor 1 (OX1R), GHSR1a, PKR1, somatostatin receptors (SSTRs), and melanin-concentrating hormone receptor 1 (MCHR1) ( Chaly et al, 2016 ; Rouault et al, 2017 ; Srisai et al, 2017 ; Wang et al, 2022 b, 2022 c). It is noteworthy that these few reported GPCRs share similarities in terms of expressional distribution with MRAP2.…”

Section: The New Exploration Of the Mrap Familymentioning

confidence: 99%

Single transmembrane GPCR modulating proteins: neither single nor simple

Wang,

Lyu,

Zhang

2023

Protein &Amp; Cell

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The discovery of G-protein coupled receptor (GPCR) accessory proteins has fundamentally redefined the pharmacological concept of GPCR signaling, demonstrating a more complex molecular basis for receptor specificity on the plasma membrane and impressionable downstream intracellular cascades. GPCR accessory proteins not only contribute to the proper folding and trafficking of receptors, but also exhibit selectable receptor preferences. The melanocortin receptor accessory proteins (MRAP1 and MRAP2) as well as receptor activity-modifying proteins (RAMPs) are two well-known single transmembrane partners for the regulation of the melanocortin receptors (MC1R-MC5R) and the glucagon receptor (GCGR), respectively. Especially, MRAP family participates in the pathological control of multiple endocrine disorders and RAMPs contribute to the endogenous regulation of glucose homeostasis. However, the precise mechanisms by which the MRAP and RAMP proteins regulate receptor signaling at the atomic resolution remain unknown. Recent progress made in the determination of RAMP2-bound GCGR complexes published on Cell (Krishna Kumar et al., 2023) unraveled the importance of RAMP2 for the promotion of extracellular receptor dynamics leading to cytoplasmic surface inactivation. Moreover, the new findings on Cell Research (Luo et al., 2023) of the adrenocorticotropic hormone (ACTH)-bound MC2R–Gs–MRAP1 complex disclosed the essential role of MRAP1 for MC2R activation and specificity of ligand recognition. In this article, we reviewed a series of key findings of MRAP proteins in the last decade, and the recent structural investigation of MRAP-MC2R and RAMP-GCGR functional complex and the expanded identification of new GPCR partners of MRAP proteins. In-depth understanding of GPCR modulation by single transmembrane accessory proteins will provide valuable insights for the therapeutic drug development to treat multiple GPCR associated human disorders.

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“…In mice, global ablation of PK2 or PKR1 leads to obesity [6]. The activation of PKRs is modulated by melanocortin receptor accessory protein 2 (MRAP2), a membrane protein that binds several G protein-coupled receptors (GPCRs) involved in the control of energy homeostasis [21][22][23][24][25][26][27][28]. The anorexigenic effect of PK2 through the binding of PKR1 is enhanced in MRAP2 knock-out (KO) mice compared to wild-type (WT) mice, demonstrating the inhibitory role of MRAP2 on PKR1 in vivo [29].…”

Section: Introductionmentioning

confidence: 99%

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2

Lattanzi,

Casella,

Fullone

et al. 2024

CIMB

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Melanocortin receptor accessory protein 2 (MRAP2) is a membrane protein that binds multiple G protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, including prokineticin receptors. These GPCRs are expressed both centrally and peripherally, and their endogenous ligands are prokineticin 1 (PK1) and prokineticin 2 (PK2). PKRs couple all G-protein subtypes, such as Gαq/11, Gαs, and Gαi, and recruit β-arrestins upon PK2 stimulation, although the interaction between PKR2 and β-arrestins does not trigger receptor internalisation. MRAP2 inhibits the anorexigenic effect of PK2 by binding PKR1 and PKR2. The aim of this work was to elucidate the role of MRAP2 in modulating PKR2-induced β-arrestin-2 recruitment and β-arrestin-mediated signalling. This study could allow the identification of new specific targets for potential new drugs useful for the treatment of the various pathologies correlated with prokineticin, in particular, obesity.

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Determination of the Interaction and Pharmacological Modulation of MCHR1 Signaling by the C-Terminus of MRAP2 Protein

Cited by 5 publications

References 27 publications

MC4R in Central and Peripheral Systems

MC4R in Central and Peripheral Systems

Single transmembrane GPCR modulating proteins: neither single nor simple

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2

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