The tale of follitropin receptor diversity: A recipe for fine tuning gonadal responses?

The original concept (dogma) of a single FSH receptor entity coupling to Gs protein to activate adenylate cyclase and producing cAMP as second messenger appears inadequate to explain pleiotropic actions of the hormone. The identification and expression of alternatively spliced gonadotropin receptors, suggest that alternative splicing could serve as a mechanism for creating receptor diversity. Studies focused on sheep and mouse gonadal tissues show that the single large gene of ∼250 kb is a modular structure whose pre-mRNA undergoes alternative splicing creating several subtypes (at least four FSH-R1 to R4 identified to date). With segments of the N-terminus that are identical different topographies are generated by differing carboxyl termini. The same gene thus produces receptor types with different motifs that can display dominant positive, dominant negative, growth factor/cytokine type and potentially soluble binding protein features. Functional relevance is shown by modulation of receptor variants during hormonal stimulation. Presence of equivalent segments of the gene in the human and bovine suggests conservation and predicts similarity in structures and function. Thus, the complex cellular biology of follitropin receptors that may interact differently with polymorphic forms (glycosylation variants) of FSH represents an intricate scheme to regulate hormone signaling.