Biased signaling in naturally occurring mutations in human melanocortin-3 receptor gene

International Journal of Biological Sciences
Fan YangYa-Xiong Tao

Abstract

The melanocortin-3 receptor (MC3R) is primarily expressed in the hypothalamus and plays an important role in the regulation of energy homeostasis. Recently, some studies demonstrated that MC3R also signals through mitogen-activated protein kinases (MAPKs), especially extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 signaling is known to alter gene expression, potentially contributing to the prolonged action of melanocortins on energy homeostasis regulation. In the present study, we performed detailed functional studies on 8 novel naturally occurring MC3R mutations recently reported, and the effects of endogenous MC3R agonist, α-melanocyte stimulating hormone (MSH), on ERK1/2 signaling on all 22 naturally occurring MC3R mutations reported to date. We found that mutants D158Y and L299V were potential pathogenic causes to obesity. Four residues, F82, D158, L249 and L299, played critical roles in different aspects of MC3R function. α-MSH exhibited balanced activity in Gs-cAMP and ERK1/2 signaling pathways in 15 of the 22 mutant MC3Rs. The other 7 mutant MC3Rs were biased to either one of the signaling pathways. In summary, we provided novel data about the structure-function relationship of MC3R, identifying residues ...Continue Reading

Citations

Jul 30, 2015·Journal of Molecular Endocrinology·Zhao YangYa-Xiong Tao
May 22, 2016·Biochimica Et Biophysica Acta·Zhao Yang, Ya-Xiong Tao
May 16, 2019·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·Sahar EhteshamDavid Meyre
Oct 28, 2019·Frontiers in Endocrinology·Wei WangYa-Xiong Tao
Aug 26, 2020·Domestic Animal Endocrinology·H-J ZhangY-X Tao
Feb 24, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Wei WangDong-Yu Guo
Sep 20, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Li-Kun YangYa-Xiong Tao
Apr 20, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Qiang MaNaiming Zhou
Sep 1, 2018·ACS Chemical Neuroscience·Xiao-Chen Yuan, Ya-Xiong Tao

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Methods Mentioned

BETA
transfection
flow cytometry

Software Mentioned

GraphPad Prism
ImageJ

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