Hypo-glycosylated human follicle-stimulating hormone (hFSH(21)) exhibits higher endocytic rate for recombinant hFSH Receptor than fully-glycosylated hFSH (hFSH(24))

Abstract

Follicle-stimulating hormone (FSH) plays an essential role in the regulation of reproduction, as FSH KO female mice are sterile. FSH regulates ovarian granulosa and testicular Sertoli cell function by binding to its cognate receptor (FSHR), a member of the G protein-coupled receptor family. Human FSH exists as a heterogeneous mixture of glycoform, differing in the number and location of β subunit glycans. Recently, it has been reported that hypo-glycosylated hFSH binds and activates hFSHR more than fully-glycosylated hFSH (Bousfield et al. Molecular and Cellular Endocrinology 382: 989-997, 2013). We analyzed the kinetics of FSH/FSH receptor complex endocytosis using 125I-hFSH21, 125I-hFSH24 glycoform tracers and recombinant hFSHR-expressing Chinese Hamster Ovarian (CHO) cells as a model system. A greater endocytic rate for hypo-glycosylated hFSH/FSH receptor complex was observed than for fully-glycosylated hFSH/FSH receptor complex. One could argue that this reflects greater receptor occupancy for hFSH21. However, increased FSH binding induced by non-steroidal allosteric modulators of the FSHR, is not attended by increased internalization. Hypo-glycosylated hFSH21 can not only occupy more FSHR binding sites, but also more effectively activates these receptors and this appears to increase the internalization rate.