Characterizing a New Mechanism in GPCR Signaling and Energy Balance

Abstract

The melanocortin signaling system, composed of five G-protein coupled receptors (GPCRs) and endogenous peptide ligands, regulates a wide range of essential physiological processes. The melanocortin 4 receptor (MC4R) is expressed predominantly in the central nervous system and is essential for maintaining feeding behavior and energy balance. Heterozygous mutations in MC4R are the most common genetic cause of human obesity. A unique feature of MC4R signaling is that it is partially regulated by its endogenous antagonist, the agouti-related peptide (AgRP). Activation of MC4R through the Gαs pathway results in an increase in cAMP and negative energy balance, whereas AgRP antagonism reduces levels of cAMP and results in positive energy balance. New research shows that melanocortin signaling is more complex than previously understood, and cannot be explained simply by agonist/antagonist modulation of the Gαs pathway. There are newly identified accessory proteins involved in the regulation of MC4R in an AgRP-dependent manner. AgRP is able to activate an inwardly-rectifying potassium channels (Kir7.1) through MC4R signaling. AgRP-induced opening of Kir7.1 hyperpolarizes MC4R neurons and decreases the frequency of action potential firing. This occurs in a G protein-independent fashion; however, the mechanism by with MC4R couples to Kir7.1 is unknown. Understanding the molecular basis of this G-protein independent signaling pathway will help to redefine the current model of melanocortin and GPCR signaling, and may lead to new concepts in the development of therapeutics aimed at treating metabolic diseases.