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

Xu, Jing; Wang, Meng; Fu, Yanbin; Zhang, Cong; Kuang, Zhe; Bian, Shan; Wu, Rui; Qu, Shen; Zhang, Chao

doi:10.3390/biology11060874

Cited by 4 publications

(3 citation statements)

References 40 publications

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“…While the inversion of the N-terminal, C-terminal, or transmembrane regions of MRAP2 did not affect dimer formation, it altered the pharmacological regulation of MC4R signaling ( Wang et al, 2021 ). And we also demonstrated that the complete reversion of the whole MRAP2 protein sequence could generate a functional novel pharmacological modulator of MC4R ( Xu et al, 2022 ).…”

Section: Characterization and Physiological Functions Of The Mrap Familymentioning

confidence: 83%

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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Section: Characterization and Physiological Functions Of The Mrap Familymentioning

confidence: 83%

Single transmembrane GPCR modulating proteins: neither single nor simple

Wang,

Lyu,

Zhang

2023

Protein &Amp; Cell

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“…Similar to the study by Motegi et al, 29 specific deletion of the MC4R gene in VGlut2 neurons caused obesity in mice. Early studies using MC4R KO mice, or MC4R agonists, 30 showed that MC4R regulates food intake independently of changes in body weight. Xu et al 27 reported a significant reduction in energy expenditure in MC4R‐deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic melanocortin‐4 receptor neurons regulate body weight

Liu

et al. 2023

The FASEB Journal

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The locus coeruleus (LC), enriched in vesicular glutamate transporter 2 (VGlut2) neurons, is a potential homeostasis‐regulating hub. However, the identity of melanocortin‐4 receptor (MC4R) neurons in the paraventricular nucleus (PVN) of the hypothalamus, PVNVGlut2::MC4R and LCVGlut2::MC4R regulation of body weight, and axonal projections of LCVGlut2 neurons remain unclear. Conditional knockout of MC4R in chimeric mice was used to confirm the effects of VGlut2. Interscapular brown adipose tissue was injected with pseudorabies virus to study the central nervous system projections. We mapped the LCVGlut2 circuitry. Based on the Cre–LoxP recombination system, specific knockdown of MC4R in VGlut2 neurons resulted in weight gain in chimeric mice. Adeno‐associated virus‐mediated knockdown of MC4R expression in the PVN and LC had potential superimposed effects on weight gain, demonstrating the importance of VGlut2 neurons. Unlike these wide‐ranging efferent projections, the PVN, hypothalamic arcuate nucleus, supraoptic nucleus of the lateral olfactory tegmental nuclei, and nucleus tractus solitarius send excitatory projections to LCVGlut2 neurons. The PVN → LC glutamatergic MC4R long‐term neural circuit positively affected weight management and could help treat obesity.

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“…Melanocortin 2 receptor accessory protein 2 (MRAP2) is a regulatory protein that is expressed in the HEK-293 cells we used [52], but not in COS-7 cells [53]. Several studies have shown that MC4R signaling is highly affected by MRAP2 [54][55][56][57][58]; therefore, the presence or rather, in the case of COS-7 cells, the absence of MRAP2 can affect results. Furthermore, the SV40 promoter used for our MC4R expression plasmids is ideal for COS-7 cells [59] but results in reduced expression in HEK-293 cells, which is wanted in our study to better resemble the physiological state.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Pharmacological Rescue of Melanocortin-4 Receptor Nonsense Mutations by Aminoglycoside

Höpfner

Paisdzior

Reininghaus

et al. 2022

Life

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The melanocortin-4 receptor (MC4R) is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. Melanocortin-4 receptor mutations prevalently cause monogenetic obesity. A possibility of overcoming stop mutations is aminoglycoside-mediated translational readthrough. Promising results were achieved in COS-7 cells, but data for human cell systems are still missing, so uncertainty surrounds this potential treatment. In transfected HEK-293 cells, we tested whether translational readthrough by aminoglycoside Geneticin combined with high-affinity ligand setmelanotide, which is effective in proopiomelanocortin or leptin receptor deficiency patients, is a treatment option for affected patients. Five MC4R nonsense mutants (W16X, Y35X_D37V, E61X, W258X, Q307X) were investigated. Confocal microscopy and cell surface expression assays revealed the importance of the mutations’ position within the MC4R. N-terminal mutants were marginally expressed independent of Geneticin treatment, whereas mutants with nonsense mutations in transmembrane helix 6 or helix 8 showed wild-type-like expression. For functional analysis, Gs and Gq/11 signaling were measured. N-terminal mutants (W16X, Y35X_D37V) showed no cAMP formation after challenge with alpha-MSH or setmelanotide, irrespective of Geneticin treatment. Similarly, Gs activation was almost impossible in W258X and Q307X with wild-type-like cell surface expression. Results for Gq/11 signaling were comparable. Based on our data, this approach improbably represents a therapeutic option.

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

Cited by 4 publications

References 40 publications

Single transmembrane GPCR modulating proteins: neither single nor simple

Single transmembrane GPCR modulating proteins: neither single nor simple

Glutamatergic melanocortin‐4 receptor neurons regulate body weight

Evaluation of Pharmacological Rescue of Melanocortin-4 Receptor Nonsense Mutations by Aminoglycoside

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