Soluble adenylyl cyclase inhibition prevents human sperm function essential for fertilization
Soluble adenylyl cyclase inhibition prevents human sperm function essential for fertilization
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DOI：
10.1093/molehr/gaab054
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发表时间：
2021-08-31
影响因子：
4
通讯作者：
Levin, Lonny R.
中科院分区：
文献类型：
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作者：
Balbach, Melanie;Ghanem, Lubna;Levin, Lonny R.
可溶性腺苷酸环化酶（sAC: ADCY10）已被遗传学证实对小鼠和人类的雄性生殖能力至关重要。在小鼠中，对休眠的尾侧附睾精子的离体研究表明，sAC是启动获能和激活运动所必需的。我们现在使用一种改进的sAC抑制剂TDI-10229，对小鼠和人类精子中的sAC功能进行全面分析。与尾侧附睾小鼠精子不同的是，人类精子是在射精后，在sAC活性已经被刺激之后收集的。除了阻止休眠小鼠精子中sAC和蛋白激酶A活性、酪氨酸磷酸化、碱化、心跳频率和顶体反应的能化诱导的刺激外，sAC抑制剂还能阻断射精精子中这些能化诱导的变化。此外，我们首次发现sAC在小鼠和人类精子顶体胞吐过程中是必需的。这些数据将sAC抑制剂定义为适合通过阴道内装置给药的非激素、按需避孕药具的候选药物。
Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.