β-Arrestin 1 Differentially Modulates cAMP and ERK Pathways Downstream of the FSH Receptor

This study compared the gonadotropin gene sequences (LH and FSH subunits) of Cynomolgus and Rhesus monkeys and produced recombinant single-chain LHβ/α and FSHβ/α proteins. The α- and FSHβ-subunit sequences were identical between species, while LHβ showed only minor synonymous differences. The recombinant hormones were successfully expressed and shown to be mainly N-glycosylated. Recombinant monkey FSHβ/α activated cAMP signaling in human FSH receptor-expressing cells, confirming its biological activity. β-arrestin 1 was found to have dual roles: its absence increased cAMP signaling (negative regulation), but it was required for ERK1/2 activation. ERK activation depended mainly on the cAMP/PKA pathway. Human and rat FSH receptors displayed different ERK activation timing, indicating species-specific signaling behavior. Overall, the study establishes a reliable system for producing functional recombinant monkey gonadotropins and clarifies how β-arrestin 1 differentially regulates FSH receptor signaling.