Glucose-regulated protein 78 binds to and regulates the melanocortin-4 receptor

Ye Ran Yoon, Tae Gul Lee, Mi Hyun Choi, Seung Woo Shin, Young Gyu Ko, Im Joo Rhyu, Dong Hoon Kim, Je Kyung Seong, Ja Hyun Baik

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling.

Original languageEnglish
Article number120
JournalExperimental and Molecular Medicine
Issue number9
Publication statusPublished - 2018 Sept 1

Bibliographical note

Funding Information:
We thank the staff of Gyerim Experimental Animal Resource Center for animal care and technical assistance. This work was supported by the Korea Mouse Phenotyping Project (Grant no: 2013M3A9D5072550 and Grant no: 2016M3A9D5A01952412) and the Science Research Center (2015R1A5A1009024) of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, Future Planning of the Republic of Korea, and by a Korea University grant.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


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