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GPCR contributor article Canonical chemokine receptors as scavenging “decoys” Shivani Sachdev, Brendan

September 2022 "Melanocortin 4 receptor (MC4R) is part of the leptin-melanocortin pathway and plays an essential role in mediating energy homeostasis. Mutations in the MC4R 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 Gs signaling properties. Recent studies introducing setmelanotide, a novel synthetic MC4R agonist, suggest a predominant role of the Gq/11 pathway regarding weight regulation. In this study, we analyzed effects of inhibiting homodimerization on Gq/11 signaling using previously reported MC4R/CB1R chimeras. NanoBRETTM studies to determine protein–protein interaction were conducted, confirming decreased homodimerization capacities of chimeric receptors in HEK293 cells. Gq/11 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 Gq/11 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." Read more at the source #DrGPCR #GPCR #IndustryNews

To achieve this, the work of Heydenreich et al. (2023) will be analysed to demonstrate how mutagenesis This distinction is essential for designing drugs that selectively target these residues to achieve desired patient with a specific variant of the β2AR gene that reduces potency might require a higher drug dose to achieve

To achieve this goal, we use a wide range of established approaches (biochemistry, cell biology, genetics

Highlights of the Week How Ligands Achieve Biased Signaling toward Arrestins Stéphanie Gaillard , Neha MC4R signaling and potentiates Kir7.1 to promote food consumption Reviews, GPCRs, and more How Ligands Achieve

Collaborations Yamina and Jacek had a deep and engaging discussion about their research interests and achievements