Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Experimental Pediatric Endocrinology, Augustenburger Platz 1, 13353 Berlin, Germany.
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Group Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, 10117 Berlin, Germany.
Biomolecules. 2022 Aug 15;12(8):1119. doi: 10.3390/biom12081119.
Melanocortin 4 receptor (MC4R) is part of the leptin-melanocortin pathway and plays an essential role in mediating energy homeostasis. Mutations in the are the most frequent monogenic cause for obesity. Due to increasing numbers of people with excess body weight, the MC4R has become a target of interest in the search of treatment options. We have previously reported that the MC4R forms homodimers, affecting receptor G signaling properties. Recent studies introducing setmelanotide, a novel synthetic MC4R agonist, suggest a predominant role of the G pathway regarding weight regulation. In this study, we analyzed effects of inhibiting homodimerization on G signaling using previously reported MC4R/CB1R chimeras. NanoBRET studies to determine protein-protein interaction were conducted, confirming decreased homodimerization capacities of chimeric receptors in HEK293 cells. G signaling of chimeric receptors was analyzed using luciferase-based reporter gene (NFAT) assays. Results demonstrate an improvement of alpha-MSH-induced NFAT signaling of chimeras, reaching the level of setmelanotide signaling at wild-type MC4R (MC4R-WT). In summary, our study shows that inhibiting homodimerization has a setmelanotide-like effect on G signaling, with chimeric receptors presenting increased potency compared to MC4R-WT. These findings indicate the potential of inhibiting MC4R homodimerization as a therapeutic target to treat obesity.
黑皮质素 4 受体（MC4R）是瘦素-黑皮质素途径的一部分，在调节能量平衡方面发挥着重要作用。的突变是肥胖症最常见的单基因原因。由于超重的人数不断增加，MC4R 已成为寻找治疗方法的目标。我们之前曾报道过 MC4R 形成同源二聚体，影响受体 G 信号转导特性。最近引入新型合成 MC4R 激动剂 setmelanotide 的研究表明，G 途径在体重调节中起着主要作用。在这项研究中，我们使用先前报道的 MC4R/CB1R 嵌合体分析了抑制同源二聚化对 G 信号转导的影响。进行了用于确定蛋白质-蛋白质相互作用的 NanoBRET 研究，证实了嵌合受体在 HEK293 细胞中同源二聚化能力降低。使用基于荧光素酶的报告基因（NFAT）测定法分析嵌合受体的 G 信号转导。结果表明，α-MSH 诱导的 NFAT 信号转导在嵌合体中得到改善，达到野生型 MC4R（MC4R-WT）中 setmelanotide 信号的水平。总之，我们的研究表明，抑制同源二聚化对 G 信号转导具有 setmelanotide 样作用，与 MC4R-WT 相比，嵌合受体的效力增加。这些发现表明抑制 MC4R 同源二聚化作为治疗肥胖症的治疗靶点具有潜力。
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