Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs.
Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs.
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DOI：
10.1096/fj.201902163r
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Vijayaraghavan S
中科院分区：
文献类型：
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作者：
Dey S;Eisa A;Kline D;Wagner FF;Abeysirigunawardena S;Vijayaraghavan S
糖原合成酶激酶3（GSK3）被鉴定为调节精子蛋白磷酸酶的酶。GSK3α对精子功能至关重要，而GSK3β则不然。缺乏GSK3α的精子表现出运动性改变，无法进行超活化，这是受精所必需的。睾丸和精子中缺乏精子特异性钙调磷酸酶（PP2B）（一种钙调节磷酸酶）的雄性小鼠也是不育的。PP2B的缺失导致附睾精子成熟和活力受损。GSK 3 α和PP 2B基因敲除小鼠的表型相似，促使我们研究精子中这两种酶之间的相互关系。必须存在高钙水平才能使具有催化活性的钙调神经磷酸酶在附睾精子成熟过程中发挥作用。与活动的附睾精子相比，不活动的附睾精子的总钙和游离钙水平较高。FK506对钙调磷酸酶的抑制导致精子GSK3的净磷酸化增加，从而降低其催化活性。FK506和GSK 3 α亚型选择性抑制剂BRD 0705也能抑制体外受精。GSK3α和精子PP2B的相关功能在附睾精子成熟和受精过程中至关重要。我们的研究结果应该能够开发针对一种或两种酶的男性避孕药。
Glycogen synthase kinase 3 (GSK3) was identified as an enzyme regulating sperm protein phosphatase. The GSK3α paralog, but not GSK3β, is essential for sperm function. Sperm lacking GSK3α display altered motility and are unable to undergo hyperactivation, which is essential for fertilization. Male mice lacking sperm specific calcineurin (PP2B), a calcium regulated phosphatase, in testis and sperm, are also infertile. Loss of PP2B results in impaired epididymal sperm maturation and motility. The phenotypes of GSK3α and PP2B knockout mice are similar, prompting us to examine the interrelationship between these two enzymes in sperm. High calcium levels must exist to permit catalytically active calcineurin to function during epididymal sperm maturation. Total and free calcium levels are high in immotile compared to motile epididymal sperm. Inhibition of calcineurin by FK506 results in an increase in the net phosphorylation and a consequent decrease in catalytic activity of sperm GSK3. The inhibitor FK506 and an isoform-selective inhibitor of GSK3α, BRD0705, also inhibited fertilization of eggs in vitro. Interrelated functions of GSK3α and sperm PP2B are essential during epididymal sperm maturation and during fertilization. Our results should enable the development of male contraceptives targeting one or both enzymes.