UMM Logo

Universitas Muhammadiyah Malang


Free Download Journals Directory


International Journal Of Bilogical Sciences

A Small Molecule Agonist THIQ as a Novel Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants

Hui Huang and Ya-Xiong Tao
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States  Corresponding author: Ya-Xiong Tao, PhD, Department of Anatomy, Physiology and Pharmacology, 212 Greene Hall, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States. Tel: 01-334-844-5396; FAX: 01-334-844-5388; Email: taoyaxi@auburn.edu
Abstract :

Although mutations in the melanocortin-4 receptor (MC4R) gene cause severe early-onset obesity, we still do not have effective approaches to correct the defects of these mutations. Several antagonists have been identified as pharmacoperones of the MC4R whereas no agonist of the MC4R has been reported. In the present study, we investigated the effect of a small molecule agonist of the MC4R, THIQ, on the cell surface expression and signaling of ten intracellularly retained MC4R mutants using different cell lines. We showed that THIQ increased the cell surface expression of three mutants (N62S, C84R, and C271Y) and two of them (N62S and C84R) had increased signaling in HEK293 cells. Interestingly, THIQ increased the signaling of two other mutants (P78L and P260Q) without increasing their cell surface expression in HEK293 cells. In neuronal cells, THIQ exhibited a more potent effect, correcting the cell surface expression and signaling of seven mutants (N62S, I69R, P78L, C84R, W174C, P260Q, and C271Y). Other mutants were not rescued by THIQ. We also showed that THIQ did not rescue MC4R mutants defective in ligand binding or signaling or one intracellularly retained mutant of the melanocortin-3 receptor. In summary, we demonstrated that a small molecule agonist acted as a pharmacoperone of the MC4R rescuing the cell surface expression and signaling of some intracellularly retained MC4R mutants.

Keywords :
G protein-coupled receptor; Melanocortin-4 receptor; Obesity; Pharmacological chaperone/Pharmacoperone; THIQ

Date Deposited : 12 Feb 2016 10:42

Last Modified : 12 Feb 2016 10:42

Official URL: http://www.ijbs.com/v10i8

Volume 10, Number 8, - 2014 , ISSN 1449-2288

Download:
Full Text Original
Abstract : pdf doc
Home | Peta Situs | Admissions | Student Research | E-Journal
Universitas Muhammadiyah Malang © 2011
Developed by Infokom UMM
Last Update : 13 December 2016 20:46Kumpulan file jurnal