Role of forward-motility-stimulating factor as an extracellular activator of soluble adenylyl cyclase

Forward-motility-stimulating factor (FMSF) is a protein, originally purified from bubaline serum, that promotes progressive motility of mature spermatozoa. FMSF binds to sperm surface receptors and activates transmembrane adenylyl cyclase (tmAC), causing a rise in intracellular cyclic AMP level ([cAMP]i) and subsequent activation of a protein kinase A/tyrosine kinase-mediated pathway that enhances forward motility. This article further evaluates how FMSF works in the caprine system, particularly identifying the stimulatory effect of this glycoprotein on soluble adenylyl cyclase (sAC). Elevated [cAMP]i, initially resulting from FMSF-dependent activation of tmAC, was associated with the release of Ca(2+) from an intracellular calcium store in the sperm head, likely via an inositol triphosphate-sensitive calcium ion channel. This peak Ca(2+) concentration of ∼125-175 nM was capable of stimulating sAC in vitro in a calmodulin-independent manner, thereby triggering more cAMP production. Our model proposes that a positive-feedback loop mediated by cAMP and Ca(2+) is established in FMSF-stimulated sperm, with cAMP playing the role of a chemical messenger at multiple steps, resulting in the observed progressive motility. Thus, FSMF stimulates a novel signaling cascade that synergistically activate both tmAC and sAC to achieve forward sperm motility.