Zn2+-stimulation of sperm capacitation and of the acrosome reaction is mediated by EGFR activation

Abstract

Extracellular zinc regulates cell proliferation via the MAP1 kinase pathway in several cell types, and has been shown to act as a signaling molecule. The testis contains a relatively high concentration of Zn(2+), required in both the early and late stages of spermatogenesis. Despite the clinical significance of this ion, its role in mature sperm cells is poorly understood. In this study, we characterized the role of Zn(2+) in sperm capacitation and in the acrosome reaction. Western blot analysis revealed the presence of ZnR of the GPR39 type in sperm cells. We previously demonstrated the presence of active epidermal growth factor receptor (EGFR) in sperm, its possible transactivation by direct activation of G-protein coupled receptor (GPCR), and its involvement in sperm capacitation and in the acrosome reaction (AR). We show here that Zn(2+) activates the EGFR during sperm capacitation, which is mediated by activation of trans-membrane adenylyl cyclase (tmAC), protein kinase A (PKA), and the tyrosine kinase, Src. Moreover, the addition of Zn(2+) to capacitated sperm caused further stimulation of EGFR and phosphatydil-inositol-3-kinase (PI3K) phosphorylation, leading to the AR. The stimulation of the AR by Zn(2+) also occurred in the absence of Ca(2+) in the incubation medium, and required the tmAC, indicating that Zn(2+) activates a GPCR. The AR stimulated by Zn(2+) is mediated by GPR39 receptor, PKA, Src and the EGFR, as well as the EGFR down-stream effectors PI3K, phospholipase C (PLC) and protein kinase C (PKC). These data support a role for extracellular zinc, acting through the ZnR, in regulating multiple signaling pathways in sperm capacitation and the acrosome reaction.

Sperm Cohort-Specific Zinc Signature Acquisition and Capacitation-Induced Zinc Flux Regulate Sperm-Oviduct and Sperm-Zona Pellucida Interactions

“…The FZ3 fluorescence localized to the bull acrosome likely represents Zn 2+ attached to or dissociated from acrosomal Zn-sensing receptor (ZnR) GPR39 of the G-protein-coupled receptor. This ZnR has been reported previously in bull spermatozoa and is believed to regulate acrosomal exocytosis [42]. Additionally, the sperm life span following the posterior-to-anterior sperm head membrane modification was relatively short (less than 5 min) and is presumed to be the time at which full molecular acquisition or competence to fertilize comes as no surprise.…”

MicroRNA in sperm from Duroc, Landrace and Yorkshire boars

“…Target genes with the highest target score (≥90) are shown (Table 7). Several target genes, including SLC9A6, AQP4, EGFR, MAP3K1, NR2C2, PTPRG, RET, ABCB9, PTEN and JAM229303132333435363738 are involved in either spermatogenesis or sperm function. We inferred that these target genes would have been up-regulated in Yorkshire and Landrace sperm, compared to Duroc sperm.…”

Spermiotoxicity of commercial condoms made from polyurethane, polyisoprene and latex, using domestic ruminants as an experimental animal model

“…This might be explained by acrosome damage associated with alterations in the sperm plasma membrane architecture. The zinc in latex and polyisoprene condoms (Depree et al ., ) might affect the acrosome reaction in some way (Michailov et al ., ).…”