Human follicle stimulating hormone (hFSH) is a gonadotropin involved in the stimulation of ovarian follicles in women and the proper maturation of sperm in men. The receptor, hFSHR, belongs to the G protein-coupled receptor class of hormone receptors and is found embedded in cell membranes. Binding of hFSH to its receptor initiates a complex downstream signaling pathway, the precise intricacies of which are still being determined. Previous research in has suggested that hFSHR is located in lipid rafts, microdomains of the membrane that are made up of a higher concentration of cholesterol, glycosphingolipids, and the protein caveolin.
To better understand the mechanism and effect of hFSHR lipid raft residency, cells from the HEK293 line were treated with a peptide mimetic of transmembrane domain 4 of hFSHR. This peptide includes a sequence consistent with a motif shown in other proteins to interact with caveolin. The putative caveolin interaction motif (phiXphiXXXXphiXXphi) was synthesized along with the HIV-TAT leader sequence to allow transmembrane passage. A second peptide where the aromatic amino acids were replaced with leucine was also used. Cells treated with the wild type peptide showed elevated basal signaling in the absence of FSH, an effect not observed with the mutant peptide.
The same cell line was also treated with two negative allosteric receptor modulators (NAMs) that have been shown to induce biased signaling of the receptor in other experiments. These modulators had an effect on hFSH action in our HEK293 cell line as well. These results suggest that receptor action can be modified using small molecules. Through further studying this signaling we hope to identify ways to control the receptor for improved methods for contraception and treatment of infertility.