Regulation of Phosphorylation of Glycogen Synthase Kinase 3 & alpha; and the Correlation with Sperm Motility in Human

Purpose: To unravel the mechanism regulating the phosphorylation of glycogen synthase kinase 3 (GSK3) and the correlation between the inhibitory phosphorylation of GSK3 & alpha; and sperm motility in human.Materials and Methods: The phosphorylation and priming phosphorylated substrate-specific kinase activity of GSK3 were ex-amined in human spermatozoa with various motility conditions.Results: In human spermatozoa, GSK3 & alpha;/& beta; was localized in the head, midpiece, and principal piece of tail and p-GSK3 & alpha;(Ser21) was enriched in the midpiece. The ratio of p-GSK3 & alpha;(Ser21)/GSK3 & alpha; was positively coupled with normal sperm motility criteria of World Health Organization. In high-motility spermatozoa, p-GSK3 & alpha;(Ser21) phosphotyrosine (p-Tyr) proteins but p-GSK3 & alpha;(Tyr279) markedly increased together with decreased kinase activity of GSK3 after incubation in Ca2+ containing medium. In high-motility spermatozoa, p-GSK3 & alpha;(Ser21) levels were negatively coupled with kinase activity of GSK3, and which was deregulated in low-motility spermatozoa. In high-motility spermatozoa, 6-bromo-indirubin-3'-oxime, an inhibitor of kinase activity of GSK3 increased p-GSK3 & alpha;(Ser21) and p-Tyr proteins. p-GSK3 & alpha;(Ser21) and p-Tyr protein levels were decreased by inhibition of PKA and Akt. Calyculin A, a protein phosphatase-1/2A inhibitor, markedly increased the p-GSK3 & alpha;(Ser21) and p-Tyr proteins, and significantly increased the motility of low-motility human spermatozoa.Conclusions: Down regulation of kinase activity of GSK3 & alpha; by inhibitory phosphorylation was positively coupled with human sperm motility, and which was regulated by Ca2+, PKA, Akt, and PP1. Small-molecule inhibitors of GSK3 and PP1 can be considered to potentiate human sperm motility.

Automated summary

The purpose of this study was to investigate the mechanism regulating the phosphorylation of glycogen synthase kinase 3 (GSK3) and its correlation with sperm motility in humans. The researchers found that the inhibitory phosphorylation of GSK3α (Ser21) was negatively correlated with its kinase activity in high-motility spermatozoa, and this correlation was regulated by Ca2+, PKA, Akt, and PP1. These findings may provide new drug targets for enhancing human sperm motility.