Résumé·s
Adequate protein folding and trafficking represent crucial processes in the proper functioning of cells.
Their integrity is ensured by highly regulated multi-step quality control mechanisms at different locations in the
protein synthesis and secretory pathway. For membrane proteins such as G protein-coupled receptors (GPCR),
folding and quality control occur mainly in the endoplasmic reticulum and the Golgi complex. Mutations in the
coding sequence of GPCR often lead to incomplete or inappropriate folding that results in their recognition and
their intracellular retention by the quality control system, preventing their targeting to the plasma membrane,
where they usually mediate their action. Given the pleiotropic roles of GPCR in recognizing many signalling
molecules(e.g., hormones, neurotransmitters, cytokines, odours, etc.), such mutations often lead to pathologies
known as conformational diseases. Among them, the best characterized were retinitis pigmentosa, nephrogenic
diabetes insipidus, hypogonadotropic hypogonadism and severe early-onset obesity resulting from mutation in
the genes coding for rhodopsin (RHO), vasopressin type 2 receptor (V2R), gonadotropin-releasing hormone
receptor (GnRHR) and melanocortin type 4 receptor (MC4R), respectively. In recent years, molecules known as
chemical and pharmacological chaperones were found to promote the proper folding, trafficking and function of
mutant forms of GPCR responsible for conformational diseases, thus opening avenues for the development of
new treatments for these ailments. Here, we briefly review the mechanisms involved in protein folding and its
quality control, and focus on the mechanism of action of GPCR-targeting pharmacological chaperones, their in
vivo action, as well as their potentials and challenges for clinical development.