A polymorphism at position 680 (N→S) of the human FSH receptor (FSHR) has been associated with an increased resistance to FSH in women bearing an S/S genotype, whereas the effects of ovarian hyperstimulation syndrome (OHSS) are more pronounced in N/N patients who also produce more oestradiol. Surprisingly, despite these differences in the FSH responsiveness of treated women, the FSH-induced cAMP response is similar for the two variants when assayed in vitro. We therefore investigated whether other components of the FSH-induced signaling network could explain those differences. We found in HEK293 cells stably expressing either variant that the S680 exhibited enhanced β-arrestin recruitment and increased internalization rate, when compared with the N680 FSHR. Comparatively, FSH-mediated activation of the N680 variant led to strikingly enhanced CREB phosphorylation and CRE-dependent transcriptional activity. Consistently, nuclear PKA activity was significantly higher with the N680 as revealed in living cells by FRET assay whereas global PKA activity was identical with both variants. In addition, PKA was found to interact with β-arrestins. Together, our data lead to a novel model where β-arrestin operates as a transporter for activated PKA, actively promoting its translocation from cytosol to nucleus. The presence of an extra S residue in the carboxy-terminal tail of the FSHR enhances the stability of β-arrestin/FSHR interaction, presumably limiting PKA translocation to the nucleus through a competition mechanism. In contrast, β-arrestin interaction with agonist-bound N680 variant is weaker and increased active PKA translocation to the nucleus promotes CREB phosphorylation and the transcription of CREB-responsive genes.