Forward motility stimulating factor (FMSF), a glycoprotein isolated from buffalo 
serum, binds to the surface of the mature sperm cells to promote their 
progressive motility. This article reports the mode of signal transduction of 
this extracellular factor in goat sperm. The mechanism was investigated by 
assaying intracellular second messenger level and forward motility in presence 
of different pharmacological modulators. Mg++-dependent Forskolin responsive 
form of transmembrane adenylyl cyclase (tmAC) of goat spermatozoa was probed for 
its involvement in FMSF action. Dideoxyadenosine, a selective inhibitor of 
tmACs, was used to identify the role of this enzyme in the scheme of 
FMSF-signaling. Involvement of the α-subunit of G-protein in this regard has 
been inspected using GTPγS. Participation of protein kinase A (PKA) and tyrosine 
kinase was checked using IP20 and genistein, respectively. FMSF promotes tmAC 
activity in a dose-dependent manner through receptor/G-protein activation to 
enhance intracellular cAMP and forward motility. Motility boosting effects of 
this glycoprotein are almost lost in presence of dideoxyadenosine. But, FMSF 
displayed substantial motility promoting activity when movement of spermatozoa 
was inhibited with KH7, the specific inhibitor of soluble adenylyl cyclase 
indicating tmAC to be the primary target of FMSF action. Involvement of cAMP in 
mediating FMSF action was confirmed by the application of dibutyryl cAMP. 
Observed motility regulatory effects with IP20 and genistein indicate 
contribution of PKA and tyrosine kinase in FMSF activity; enhanced 
phosphorylation of a tyrosine containing ≈50 kDa protein was detected in this 
regard. FMSF initiates a novel signaling cascade to stimulate tmAC activity that 
augments intracellular cAMP, which through downstream crosstalk of 
phosphokinases leads to enhanced forward motility in mature spermatozoa. Thus, 
this article for the first time describes conventional tmAC-dependent profound 
activation of progressive motility by a physiologic extracellular factor in a 
mammalian species.