A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function.
A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function.
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精子特异性钾通道SLO3的选择性抑制剂会损害人类精子功能。
DOI：
10.1073/pnas.2212338120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
为了使卵子受精，老鼠和人类的精子都必须经历膜超极化。在小鼠精子中，超极化是由精子特有的钾(K+)通道SL03激活引起的。在人类精子中，超极化是否依赖于SLO_3或普遍存在的K+通道SLO_1尚不清楚，因为尚未发现选择性的SLO_3抑制剂或SLO_3突变。在这里，我们鉴定了一种选择性的SLO_3抑制剂，并证明了它能阻断人类精子的K+电流、超极化以及受精所必需的下游过程。因此，SLO_3在人类男性生育能力中起着关键作用，SLO_3抑制剂具有避孕潜力，SLO_3突变可能导致一些特发性男性不育病例。为了使卵母细胞受精，小鼠和人类精子的膜电位都必须超极化(内部变得更负)。确定这种超极化的分子机制对于开发新的避孕方法和发现特发性男性不育的原因至关重要。在小鼠精子中，超极化是由精子特异性钾(K+)通道SL03的激活引起的[C.M.Santi等人，.FEBS Lett。584、1041-1046(2010)]。在人类精子中，超极化是否依赖于SL03或普遍存在的K+通道SLO1一直不清楚[N.Mannowetz，N.M.Naidoo，S.A.S.Choo，J.F.Smith，P.V.Lishko，eLife 2，e01009(2013)，C.Brenker等人，TheeLife 3，e01438(2014)，以及S.A.Mansell，S.J.Publicover，C.L.R.Barratt，S.M.Wilson，J.Mol。哼。是Reprod。20,392-408(2014)]。在这项工作中，我们发现了第一个选择性抑制人SLO_3的药物--VU0546110-，并证明它能完全阻断人精子的异种SLO_3电流和内源性K~+电流。这种化合物还防止精子超极化和经历过度激活的运动和诱导的顶体反应，这是使卵子受精所必需的。我们的结论是，SLO_3是导致超极化的唯一K+通道，对人类精子的受精能力有重要贡献。此外，SL03是避孕发育的一个很好的候选基因，该基因的突变可能是特发性男性不育的原因之一。
To fertilize an egg, both mouse and human sperm must undergo membrane hyperpolarization. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K+) channel SLO3. In human sperm, it is unclear whether hyperpolarization depends on SLO3 or the ubiquitous K+ channel SLO1, as no selective SLO3 inhibitors or SLO3 mutations have been identified. Here, we identified a selective SLO3 inhibitor and demonstrated that it blocked human sperm K+ currents, hyperpolarization, and downstream processes essential for fertilization. Therefore, SLO3 has a key role in human male fertility, SLO3 inhibitors have contraceptive potential, and SLO3 mutations could cause some cases of idiopathic male infertility. To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining the molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods and detecting causes of idiopathic male infertility. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K+) channel SLO3 [C. M. Santi et al., FEBS Lett. 584, 1041–1046 (2010)]. In human sperm, it has long been unclear whether hyperpolarization depends on SLO3 or the ubiquitous K+ channel SLO1 [N. Mannowetz, N. M. Naidoo, S. A. S. Choo, J. F. Smith, P. V. Lishko, Elife 2, e01009 (2013), C. Brenker et al., Elife 3, e01438 (2014), and S. A. Mansell, S. J. Publicover, C. L. R. Barratt, S. M. Wilson, Mol. Hum. Reprod. 20, 392–408 (2014)]. In this work, we identified the first selective inhibitor for human SLO3—VU0546110—and showed that it completely blocked heterologous SLO3 currents and endogenous K+ currents in human sperm. This compound also prevented sperm from hyperpolarizing and undergoing hyperactivated motility and induced acrosome reaction, which are necessary to fertilize an egg. We conclude that SLO3 is the sole K+ channel responsible for hyperpolarization and significantly contributes to the fertilizing ability of human sperm. Moreover, SLO3 is a good candidate for contraceptive development, and mutation of this gene is a possible cause of idiopathic male infertility.
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影响因子：
5.6
作者：
Raphemot R;Lonergan DF;Nguyen TT;Utley T;Lewis LM;Kadakia R;Weaver CD;Gogliotti R;Hopkins C;Lindsley CW;Denton JS
通讯作者：
Denton JS
影响因子：
3.5
作者：
GONZALEZMARTINEZ, M;DARSZON, A
通讯作者：
DARSZON, A
DOI：
10.1073/pnas.1215078109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Leonetti, Manuel D.;Yuan, Peng;MacKinnon, Roderick
通讯作者：
MacKinnon, Roderick
影响因子：
2.4
作者：
Lippiat, JD;Standen, NB;Davies, NW
通讯作者：
Davies, NW
影响因子：
6.1
作者：
Liu, Ruyi;Yan, Zheng;Kuang, Yanping
通讯作者：
Kuang, Yanping