Targeting melanocortin‐4 receptor (MC4R) agonists to the endoplasmic reticulum (ER) as a potential approach to obesity therapy

Abstract

Melanocortin‐4 receptor (MC4R) is a G‐protein coupled receptor (GPCR) expressed in the hypothalamus where it controls food intake. Agonist binding, including that of natural agonist alphamelanocyte stimulating hormone (α‐MSH), stimulates receptor activity and suppresses appetite. Previous studies found that MC4R undergoes agonist‐mediated desensitization, and treatment with extracellular MC4R agonists led to tachyphylaxis in mice. Here, we use Neuro2a cells expressing HA‐MC4R‐GFP to study receptor localization and function by immunofluorescence microscopy and ELISA. We find that ER‐targeted α‐MSH binds to MC4R in the ER, traffics to the cell surface with the receptor, and induces constant receptor activity. After internalization, the receptor escapes routing to the lysosomes and desensitization, consequently the signal generated maintains maximal amplitude. Most naturally occurring MC4R mutations in humans and mice lead to MC4R retention in the ER and cause obesity. Expression of ER‐targeted α‐MSH doubles traffic of obesity‐linked MC4R I316S to the cell surface. We conclude that targeting of α‐MSH to the ER is a novel approach to promote MC4R signaling without desensitization and to rescue traffic of obesity‐linked MC4R variants to the cell surface.