β-arrestins and biased signaling in gonadotropin receptors
Résumé
Gonadotropin receptors include the follicle stimulating hormone receptor (FSHR) and the luteinizing hormone/choriogonadotropin receptor (LHCGR), both belong to the G protein- coupled receptor (GPCR) superfamily and being essential to reproduction. FSHR is activated by follicle stimulating hormone (FSH) while LHCGR is activated by either luteinizing hormone (LH) or choriogonadotropin (CG). Upon ligand binding, gonadotropin receptors undergo conformational changes that leads to the activation of the heterotrimeric G protein, resulting in the production of different second messengers. Gonadotropin receptors can also recruit and bind β-arrestins. This particular class of scaffold proteins were initially identified to mediate GPCRs desensitization and recycling, but it is now well established that β-arrestins can also initiate Gs- independent signalling by assembling signalling modules. Furthermore, new advances in structural biology and biophysical techniques has revealed novel activation mechanisms in the way β-arrestins and G proteins control signalling in time and space. The ability of different ligands to preferentially elicit G- or β-arrestin-mediated signalling is known as functional selectivity or biased signalling. This new concept has switched the view of pharmacology efficacy from monodimentional to multidimensional. Biased signalling offers the possibility to separate therapeutic benefits of a drug from its adverse effects. The proof of concept that gonadotropin receptors can be subjected to biased signalling is now established. The challenge will now be the design of molecules that can specifically activate beneficial signalling pathway at gonadotropin receptors while reducing or abolishing those leading to side effects. Such strategy could for instance lead to improved treatments for infertility.