A Small Molecule Agonist THIQ as a Novel Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants

Huang, Hui; Tao, Ya-Xiong

doi:10.7150/ijbs.9625

Cited by 29 publications

(17 citation statements)

References 36 publications

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“…The phenotype of Mc3r KO might even be dependent upon the presence of MC4R. A number of MC3R and MC4R agonists have been developed, yet none of them has demonstrated satisfactory selectivity 12 49 . It is important to identify more selective agonists for MC3R and MC4R in order to elucidate their precise physiological functions in vivo .…”

Section: Discussionmentioning

confidence: 99%

Effects of Melanocortin 3 and 4 Receptor Deficiency on Energy Homeostasis in Rats

You¹,

Hu²,

Chen³

et al. 2016

Sci Rep

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Melanocortin-3 and 4 receptors (MC3R and MC4R) can regulate energy homeostasis, but their respective roles especially the functions of MC3R need more exploration. Here Mc3r and Mc4r single and double knockout (DKO) rats were generated using CRISPR-Cas9 system. Metabolic phenotypes were examined and data were compared systematically. Mc3r KO rats displayed hypophagia and decreased body weight, while Mc4r KO and DKO exhibited hyperphagia and increased body weight. All three mutants showed increased white adipose tissue mass and adipocyte size. Interestingly, although Mc3r KO did not show a significant elevation in lipids as seen in Mc4r KO, DKO displayed even higher lipid levels than Mc4r KO. DKO also showed more severe glucose intolerance and hyperglycaemia than Mc4r KO. These data demonstrated MC3R deficiency caused a reduction of food intake and body weight, whereas at the same time exhibited additive effects on top of MC4R deficiency on lipid and glucose metabolism. This is the first phenotypic analysis and systematic comparison of Mc3r KO, Mc4r KO and DKO rats on a homogenous genetic background. These mutant rats will be important in defining the complicated signalling pathways of MC3R and MC4R. Both Mc4r KO and DKO are good models for obesity and diabetes research.

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Section: Discussionmentioning

confidence: 99%

Effects of Melanocortin 3 and 4 Receptor Deficiency on Energy Homeostasis in Rats

You¹,

Hu²,

Chen³

et al. 2016

Sci Rep

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show abstract

“…Although this is the first comprehensive study on biased signaling in naturally occurring mutations in the MC4R , these findings need to be further confirmed in neuronal cells since the MC4R is expressed primarily in the central nervous system in vivo . Our recent studies on the pharmacoperones for the MC4R compared the rescuing efficacy in HEK293 cells and neuronal cells 58 , 59 . Our results showed that although the results are very similar, a few differences indeed are observed.…”

Section: Discussionmentioning

confidence: 99%

Defect in MAPK Signaling As a Cause for Monogenic Obesity Caused By Inactivating Mutations in the Melanocortin-4 Receptor Gene

He¹,

Tao²

2014

Int. J. Biol. Sci.

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The melanocortin-4 receptor (MC4R) is a Family A G protein-coupled receptor that plays an essential role in regulating energy homeostasis, including both energy intake and expenditure. Mutations leading to a reduced MC4R function confer a major gene effect for obesity. More than 170 distinct mutations have been identified in humans. In addition to the conventional Gs-stimulated cAMP pathway, the MC4R also activates MAPKs, especially ERK1/2. We also showed there is biased signaling in the two signaling pathways, with inverse agonists in the Gs-cAMP pathway acting as agonists for the ERK1/2 pathway. In the current study, we sought to determine whether defects in basal or agonist-induced ERK1/2 activation in MC4R mutants might potentially contribute to obesity pathogenesis in patients carrying these mutations. The constitutive and ligand-stimulated ERK1/2 activation were measured in wild type and 73 naturally occurring MC4R mutations. We showed that nineteen mutants had significantly decreased basal pERK1/2 level, and five Class V variants (where no functional defects have been identified previously), C40R, V50M, T112M, A154D and S295P, had impaired ligand-stimulated ERK1/2 activation. Our studies demonstrated for the first time that decreased basal or ligand-stimulated ERK1/2 signaling might contribute to obesity pathogenesis caused by mutations in the MC4R gene. We also observed biased signaling in 25 naturally occurring mutations in the Gs-cAMP and ERK1/2 pathways.

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“…For instance, the PC activity of certain agonists may be offset by their effects on activation-induced internalization, or through inhibition of receptor recycling. 816,839,840,864 Thus, in some cases allosteric PCs may offer the most promising therapeutic potential. It should also be added that the cognate ligands of many orphan receptors have yet to be discovered, which significantly limits currently available avenues for medicinal chemistry.…”

Section: Small Molecule Manipulation Of Membrane Protein Foldingmentioning

confidence: 99%

Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

et al. 2019

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Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis networks mediate MP folding and manage misfolding in the cell. When combined with results from genomic sequencing, these studies have established paradigms for how MP folding and misfolding are linked to the molecular etiologies of a variety of diseases. This emerging framework has paved the way for the development of a new class of small molecule “pharmacological chaperones” that bind to and stabilize misfolded MP variants, some of which are now in clinical use. In this review, we comprehensively outline current perspectives on the folding and misfolding of integral MPs as well as the mechanisms of cellular MP quality control. Based on these perspectives, we highlight new opportunities for innovations that bridge our molecular understanding of the energetics of MP folding with the nuanced complexity of biological systems. Given the many linkages between MP misfolding and human disease, we also examine some of the exciting opportunities to leverage these advances to address emerging challenges in the development of therapeutics and precision medicine.

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A Small Molecule Agonist THIQ as a Novel Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants

Cited by 29 publications

References 36 publications

Effects of Melanocortin 3 and 4 Receptor Deficiency on Energy Homeostasis in Rats

Effects of Melanocortin 3 and 4 Receptor Deficiency on Energy Homeostasis in Rats

Defect in MAPK Signaling As a Cause for Monogenic Obesity Caused By Inactivating Mutations in the Melanocortin-4 Receptor Gene

Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

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