β-arrestins and biased signaling in gonadotropin receptors

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 are 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 lead 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 signaling by assembling signaling modules. Furthermore, new advances in structural biology and biophysical techniques have revealed novel activation mechanisms allowing β-arrestins and G proteins to control signaling in time and space. The ability of different ligands to preferentially elicit G- or β-arrestin-mediated signaling is known as functional selectivity or biased signaling. This new concept has switched the view of pharmacology efficacy from monodimensional to multidimensional. Biased signaling 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 signaling is now established. The challenge will now be the design of molecules that can specifically activate beneficial signaling pathway at gonadotropin receptors while reducing or abolishing those leading to side effects. Such strategy could for instance lead to improved treatments for infertility.