Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity.

Supplemental Data Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity

Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity.

The melanocortin-4 receptor (MC4R) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of alpha-MSH to the MC4R leads to increased cAMP production. Recent pharmacological and genetic studies have provided compelling evidence that MC4R is an important regulator of food intake and energy homeostasis. Allelic variants of MC4R were reported in some children with early-o...

Pharmacological chaperones increase the cell-surface expression of intracellularly retained mutants of the melanocortin 4 receptor with unique rescuing efficacy profiles.

Mutated versions of membrane proteins often fail to express at the plasma membrane, but instead are trapped in the secretory pathway, resulting in disease. The retention of these mutant proteins is thought to result from local misfolding, which prevents export from the ER (endoplasmic reticulum), targeting the receptor for degradation via the ER-associated quality control system. The rhodopsin-...

Ipsen 5i is a Novel Potent Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants

Inactivating mutations of the melanocortin-4 receptor (MC4R) cause early-onset severe obesity in humans. Comprehensive functional studies show that most of the inactivating mutants of the MC4R are retained intracellularly. In the present study, we investigated whether a small molecule inverse agonist of the MC4R, Ipsen 5i, could act as a pharmacoperone and correct the cell surface expression an...

Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients

As the most common monogenic form of human obesity, about 130 naturally occurring melanocortin-4 receptor (MC4R) gene mutations have been identified. In this study, we reported detailed functional characterization of 10 novel human MC4R (hMC4R) mutants including R7C, C84R, S127L, S136F, W174C, A219V, P230L, F261S, I317V and L325F. Flow cytometry experiments showed that six mutants, including R7...