Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

Brouwers B,Laurin Sa,Marti-Solano M,De Oliveira Em,Babu Mm,Wasiluk N,Daly Ca,Bouvier M,Ayinampudi V,Keogh Jm,Henning E,Mokrosiński J,Clarke D,Monteiro Fbf,Plouffe B,Farooqi Is,Bounds R,Houston S

doi:10.1530/ey.18.11.3

Abstract

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

Highlights

Obesity-associated metabolic complications such as type 2 diabetes and cardiovascular disease contribute to significant morbidity, mortality, and health care costs (Heymsfield and Wadden, 2017)
We focused on the brain-expressed Melanocortin-4 Receptor (MC4R), a G-protein-coupled receptors (GPCRs) that plays a pivotal role in weight regulation and is a major target for drug development
MC4R mutations alter membrane expression, endocytosis, and trafficking To quantitatively assess endocytosis and intracellular trafficking in live cells, we used enhanced bystander bioluminescence resonance energy transfer-based sensors that rely on the transfer of energy between a bioluminescent donor, Renilla luciferase (RLuc), and a fluorescent acceptor, green fluorescent protein (Renilla GFP [rGFP]) (Namkung et al, 2016)

Summary

Introduction

Obesity-associated metabolic complications such as type 2 diabetes and cardiovascular disease contribute to significant morbidity, mortality, and health care costs (Heymsfield and Wadden, 2017). With multiple potentially druggable sites accessible at the cell surface (Hauser et al, 2017) and informed by the recently published 3D structure of MC4R (Yu et al, 2020) that provides a template for structurebased drug discovery, it is timely to investigate new opportunities to target MC4R for weight loss therapy. It is well-established that binding of Pro-opiomelanocortin (POMC)-derived peptides (a-/b-MSH [melanocyte-stimulating hormone]) to membrane-bound MC4R activates G proteins (Gas) and stimulates the production of cyclic AMP (cAMP) to reduce food intake in the fed state (Schwartz et al, 2000). Endocytosis of GPCRs contributes to mitogen-activated protein kinase (MAPK) pathway

Methods

Results

Discussion

Conclusion