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Role of the Glycogen Synthase Kinase 3-Cyclic AMP/Protein Kinase A in the Immobilization of Human Sperm by Tideglusib

  • Reproductive Biology: Original Article
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Abstract 

Tideglusib is considered to be a promising alternative to nonyl alcohol-9 contraceptives. Previous studies have demonstrated that the rapid spermicidal effect of tideglusib at a high concentration (≥ 10 μM) may occur through detergent-like activity; however, the effect of low concentrations of tideglusib (< 5 μM) on sperm is unknown. We explored the intracellular mechanism of tideglusib (< 5 μM) on the immobilization of human sperm by exploring related signaling pathways in human sperm. After treatment with tideglusib (1.25 μM) for 2 h, sperm motility rate decreased to 0, while sperm membrane integrity rate was 70%. Protein tyrosine phosphorylation level and intracellular cyclic adenosine 3,5-monophosphate (cAMP) concentration decreased significantly compared to those in the control group. Isobutylmethylxanthine and 8-Bromo-cAMP relieved the inhibition of spermatozoa tyrosine phosphorylation, while tyrosine phosphorylation of sperm protein in the H89 and CALP1 treatment groups was significantly inhibited, and there was no difference in the tideglusib treatment group. H-89 and CALP1 reduced the level of serine phosphorylation of GSK-3α/β (Ser21/9), while its level was enhanced by IBMX and 8-Bromo-cAMP. Our results show the existence of the GSK3-cAMP/PKA regulatory loop in human sperm, which may mediate the immobilization effect of tideglusib at low of concentrations (e.g., 1.25 μM) on sperm motility.

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All study data can be provided upon request.

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Funding

This work was supported by the National Natural Science Foundation of China (grant number 81671508) and the National Key Research and Development Program of China (grant number 2016YFC1000905).

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Authors and Affiliations

  1. NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Weiwei Wang, Lina Guo, Yuhua Li, Yiting Yang & Hua Diao

  2. College of Chemistry and Chemical Engineering, Donghua University, Shanghai, 201620, China

    Bingbing Jiang, Xin Ye & Zhiyu Shao

  3. Reproductive Medicine Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Bin Yan & Suying Liu

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  1. Weiwei Wang
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  6. Xin Ye
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Contributions

Zhiyu Shao and Hua Diao designed and supervised this study. Weiwei Wang, Bingbing Jiang, and Bin Yan collected clinical information and analyzed the data. Bin Yan, Yiting Yang, and Suying Liu recruited the participants and collected clinical information. Yuhua Li and Lina Guo performed the Western blot experiments. Weiwei Wang and Lina Guo analyzed the data and wrote the manuscript. All other authors reviewed, corrected, and approved the final manuscript.

Corresponding authors

Correspondence to Zhiyu Shao or Hua Diao.

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The Institutional Ethics Committee of Shanghai Institute for Biomedical and Pharmaceutical Technologies (SIBPT, Shanghai, China) approved this study (approved No. PJ2018-24).

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Wang, W., Guo, L., Jiang, B. et al. Role of the Glycogen Synthase Kinase 3-Cyclic AMP/Protein Kinase A in the Immobilization of Human Sperm by Tideglusib. Reprod. Sci. 30, 1281–1290 (2023). https://doi.org/10.1007/s43032-022-01086-8

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