# The role of accessory proteins and co‐factors in regulation of melanocortin‐4 receptor signalling: An update

## TL;DR

This paper reviews how accessory proteins and cofactors influence the melanocortin-4 receptor's role in appetite and energy balance, with implications for obesity.

## Contribution

The paper provides an updated overview of newly identified proteins and cofactors regulating MC4R trafficking and signaling.

## Key findings

- Calcium is a critical cofactor for MC4R agonist binding and function.
- Transmembrane proteins modulate MC4R activity and cell surface expression.
- Gs and Gq/11 pathways may differentially affect food intake and cardiovascular function.

## Abstract

The melanocortin‐4 receptor (MC4R) is a G protein‐coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by Gs and Gq/11 pathways may have differential effects on food intake, weight gain and cardiovascular function. We also summarise recent studies of MC4R expression at primary cilia, receptor oligomerisation, newly identified proteins that regulate MC4R cell surface expression, and briefly discuss novel endogenous agonists.