BACKGROUND Intensive research on sperm ion channels has identified members of several ion channel families in both mouse and human sperm. Gene knock-out studies have unequivocally demonstrated the importance of the calcium and potassium conductances in sperm for fertility. In both species, the calcium current is carried by the highly complex cation channel of sperm (CatSper). In mouse sperm, the potassium current has been conclusively shown to be carried by a channel consisting of the pore forming subunit SLO3 and auxiliary subunit leucine-rich repeat-containing 52 (LRRC52). However, in human sperm it is controversial whether the pore forming subunit of the channel is composed of SLO3 and/or SLO1. Deciphering the role of the proton-specific Hv1 channel is more challenging as it is only expressed in human sperm. However, definitive evidence for a role in, and importance for, human fertility can only be determined through studies using clinical samples. OBJECTIVE AND RATIONALE This review aims to provide insight into the role of sperm ion channels in human fertilization as evidenced from recent studies of sperm from infertile men. We also summarize the key discoveries from mouse ion channel knock-out models and contrast the properties of mouse and human CatSper and potassium currents. We detail the evidence for, and consequences of, defective ion channels in human sperm and discuss hypotheses to explain how defects arise and why affected sperm have impaired fertilization potential. SEARCH METHODS Relevant studies were identified using PubMed and were limited to ion channels that have been characterized in mouse and human sperm. Additional notable examples from other species are included as appropriate. OUTCOMES There are now well-documented fundamental differences between the properties of CatSper and potassium channel currents in mouse and human sperm. However, in both species, sperm lacking either channel cannot fertilize in vivo and CatSper-null sperm also fail to fertilize at IVF. Sperm-lacking potassium currents are capable of fertilizing at IVF, albeit at a much lower rate. However, additional complex and heterogeneous ion channel dysfunction has been reported in sperm from infertile men, the causes of which are unknown. Similarly, the nature of the functional impairment of affected patient sperm remains elusive. There are no reports of studies of Hv1 in human sperm from infertile men. WIDER IMPLICATIONS Recent studies using sperm from infertile men have given new insight and critical evidence supporting the supposition that calcium and potassium conductances are essential for human fertility. However, it should be highlighted that many fundamental questions remain regarding the nature of molecular and functional defects in sperm with dysfunctional ion channels. The development and application of advanced technologies remains a necessity to progress basic and clinical research in this area, with the aim of providing effective screening methodologies to identify and develop treatments for affected men in order to help prevent failed ART cycles. Conversely, development of drugs that block calcium and/or potassium conductances in sperm is a plausible strategy for producing sperm-specific contraceptives.

中文翻译：

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人类精子离子通道（功能障碍）：对受精的影响。


背景技术对精子离子通道的深入研究已鉴定出小鼠和人类精子中几个离子通道家族的成员。基因敲除研究明确证明了精子中钙和钾电导对生育能力的重要性。在这两个物种中，钙电流均由高度复杂的精子阳离子通道 (CatSper) 携带。在小鼠精子中，钾电流已被最终证明是由孔形成亚基 SLO3 和富含亮氨酸重复序列的辅助亚基 52 (LRRC52) 组成的通道携带的。然而，在人类精子中，通道的成孔亚基是否由 SLO3 和/或 SLO1 组成仍存在争议。破译质子特异性 Hv1 通道的作用更具挑战性，因为它仅在人类精子中表达。然而，关于人类生育力的作用和重要性的明确证据只能通过使用临床样本的研究来确定。目的和基本原理本综述旨在深入了解精子离子通道在人类受精中的作用，最近对不育男性精子的研究证明了这一点。我们还总结了小鼠离子通道敲除模型的关键发现，并对比了小鼠和人类 CatSper 和钾电流的特性。我们详细介绍了人类精子中离子通道缺陷的证据及其后果，并讨论了一些假设，以解释缺陷是如何产生的以及为什么受影响的精子会损害受精潜力。搜索方法 使用 PubMed 确定相关研究，并且仅限于已在小鼠和人类精子中表征的离子通道。其他物种的其他值得注意的例子也酌情包括在内。 结果 目前，小鼠和人类精子中 CatSper 的特性和钾通道电流之间存在根本差异，这些差异已得到充分记录。然而，在这两个物种中，缺乏任一通道的精子都无法在体内受精，并且 CatSper 缺失的精子在体外受精时也无法受精。缺乏钾的精子流能够在体外受精时受精，尽管速度要低得多。然而，据报道，不育男性的精子中存在其他复杂且异质的离子通道功能障碍，其原因尚不清楚。同样，受影响的患者精子功能受损的本质仍然难以捉摸。目前还没有关于不育男性精子中 Hv1 的研究报告。更广泛的影响 最近使用不育男性精子进行的研究提供了新的见解和关键证据，支持钙和钾电导对于人类生育能力至关重要的假设。然而，应该强调的是，关于离子通道功能失调的精子的分子和功能缺陷的性质，仍然存在许多基本问题。先进技术的开发和应用仍然是推进该领域基础和临床研究的必要条件，目的是提供有效的筛查方法来识别和开发针对受影响男性的治疗方法，以帮助预防 ART 周期失败。相反，开发阻断精子中钙和/或钾电导的药物是生产精子特异性避孕药的一种可行策略。