TY  - JOUR
A1  - Paisdzior, Sarah
A1  - Dimitriou, Ioanna Maria
A1  - Schöpe, Paul Curtis
A1  - Annibale, Paolo
A1  - Scheerer, Patrick
A1  - Krude, Heiko
A1  - Lohse, Martin J.
A1  - Biebermann, Heike
A1  - Kühnen, Peter
T1  - Differential signaling profiles of MC4R mutations with three different ligands
JF  - International Journal of Molecular Sciences
N2  - 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 G\(_S\)-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 G\(_S\) loss-of-function (S127L) and a G\(_S\) 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 G\(_{q/11}\) 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.
KW  - Melanocortin 4 receptor (MC4R)
KW  - Melanocyte stimulating hormones MSH
KW  - G protein coupled receptor (GPCR)
KW  - biased signaling
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285108
SN  - 1422-0067
VL  - 21
IS  - 4
ER  -