Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

Int J Mol Sci. 2020 Feb 12;21(4):1224. doi: 10.3390/ijms21041224.

Abstract

The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin-melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.

Keywords: G protein coupled receptor (GPCR); Melanocortin 4 receptor (MC4R); Melanocyte stimulating hormones MSH; biased signaling.

MeSH terms

  • Amino Acid Sequence
  • Cyclic AMP / metabolism
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Leptin / metabolism
  • Ligands
  • Melanocortins / metabolism
  • Models, Theoretical
  • Mutation*
  • Obesity / genetics
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Receptor, Melanocortin, Type 4 / genetics*
  • Receptor, Melanocortin, Type 4 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology*
  • alpha-MSH / metabolism

Substances

  • Leptin
  • Ligands
  • MC4R protein, human
  • Melanocortins
  • Receptor, Melanocortin, Type 4
  • Receptors, G-Protein-Coupled
  • alpha-MSH
  • Cyclic AMP