Biased signaling at neural melanocortin receptors in regulation of energy homeostasis

Abstract

The global prevalence of obesity highlights the importance of understanding on regulation of energy homeostasis. The central melanocortin system is an important intersection connecting the neural pathways controlling satiety and energy expenditure to regulate energy homeostasis by sensing and integrating the signals of external stimuli. In this system, neural melanocortin receptors, melanocortin-3 and -4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy homeostasis. Recently, multiple intracellular signaling pathways and biased signaling at neural MCRs have been discovered, providing new insights into neural MCR signaling. This review attempts to summarize biased signaling including biased receptor mutants (both naturally occurring and lab-generated) and biased ligands at neural MCRs, and to provide a better understanding of obesity pathogenesis and new therapeutic implications for obesity treatment.

The constitutive activity of melanocortin‐4 receptors in cAMP pathway is allosterically modulated by zinc and copper ions

“…As Cu 2+ has biphasic response cAMP response, the classical Schild analysis could not be used to study its mode of action, but HS024 could be used to block the inverse agonistic response of the copper ions in a concentration‐dependent manner. This result once again confirms that Cu 2+ ions indeed modulate the signal transduction of MC 4 R. It is important to mention, that all these studies were directed to the activation of cAMP signaling pathway, but it is known that MC 4 R can activate also other G proteins and ERK1/2 pathway (Yang and Tao, ), but how these ions affect these systems remains for the further studies.…”

“…The complexity of the MC 4 R system is also connected with its high constitutive activity, that is, agonist‐independent signaling, and signaling bias involving different response pathways (Tao, ; Yang and Tao, ). The level of GPCR basal activity plays a critical role in determining the ligand‐binding properties and signaling spectrum of the receptors (Kenakin, ; Bond and IJzerman ).…”

Obesity‐associated mutant melanocortin‐4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects

“…However, many peptide and small molecule drugs targeting MC4R have failed in clinical trials as a result of a target‐mediated increase in blood pressure . The growing interest in biased signalling in GPCR drug discovery highlights the urgency to explore novel signalling pathways when considering target‐specific therapeutics . Interestingly, a subset of MC4R mutations in humans is associated with the development of obesity, yet these have been reported to couple normally to Gα s .…”

“…[26][27][28] The growing interest in biased signalling in GPCR drug discovery highlights the urgency to explore novel signalling pathways when considering target-specific therapeutics. [32][33][34][35][36] Interestingly, a subset of MC4R mutations in humans is associated with the development of obesity, yet these have been reported to couple normally to Gα s .…”

Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency

“…complex than previously thought including evidence of biased signaling [38] and evidence for diverse ligands exhibiting distinct temporal cellular signaling selectivity [39].…”