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

Abstract

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.

Myeloid-Derived Suppressor Cells as Target of Phosphodiesterase-5 Inhibitors in Host-Directed Therapeutics for Tuberculosis

“…c-di-AMP is recognized via macrophage cytosolic surveillance pathways as a pathogen-associated molecular pattern (PAMP). Microbial c-di-AMP production benefits the host by stimulation of autophagy as previously indicated in animal models where M.tb expressing excess c-di-AMP displayed loss of pathogenicity (12). Taken together, targeting the network of cAMP-mediated signaling pathways with repurposed drugs could reduce bacterial survival during M.tb infection.…”

“…This fosters bacterial survival by promoting necrosis and granuloma formation (10). Cyclic-di-adenosine monophosphate (c-di-AMP), a double-edged sword, M.tbderived secondary messenger, interferes with host immune signaling pathways (12). Through STING-IRF3 signaling pathway, c-di-AMP induces type I interferon, benefiting the microbe through enhanced immunopathology (13).…”

Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs

“…This suggestion is based on studies in bovine which showed that free and total calcium are remarkably high in caput sperm. 37,38 We used dual wavelength monitoring to measure free calcium levels in mouse caput and caudal epididymal sperm. 37 We wished to confirm these findings.…”

“…Dual wavelength monitoring using the ratio of emission from excitation at two different wavelengths is now the preferred method. 37,38 We used dual wavelength monitoring to measure free calcium levels in mouse caput and caudal epididymal sperm. Figure 2A Figure 2B illustrates that the free calcium is nearly threefold higher in caput compared caudal epididymal sperm ~900 nM compared to 300 nM in caudal sperm.…”

Signaling pathways involved in human sperm hyperactivated motility stimulated by Zn2+

“…The presence of active GPCR in sperm supports the functionality of tmAC in sperm. Further support for the presence of active tmAC in sperm was presented by Dey, Roy, Majumder, Mukherjee and Bhattacharyya (), who demonstrated that forward‐motility‐stimulating factor activates tmAC. In amphibian sperm motility, PKA activation is also stimulated by tmAC (O’Brien, Krapf, Cabada, Visconti, & Arranz, ).…”