离子通道与男性生殖：从生理调控到不孕诊疗

Ion channels and male reproduction: from physiological regulation to diagnosis and treatment of infertility

摘要

全球不孕症患病率升高,其中由男性因素引起的不孕约占50%以上。男性不育的重要原因之一是精子功能或形态异常,而一枚健康精子的生发、成熟与功能的发挥高度依赖离子通道蛋白。本文回顾了在精子发生、成熟、活化过程中直接或间接参与的离子通道,重点总结了CatSper、碳酸氢盐转运体（SLC4/SLC26）、钠氢交换体（NHEs）以及HVCN1等通道蛋白在胞内碱化、Ca²⁺内流等过程中发挥的作用,并归纳了间接参与精子发生、成熟的通道蛋白,如水通道蛋白（AQP3/7/8/9）、CFTR、CLC-2等。它们通过调节生精小管液体分泌、睾酮合成,为精子成熟、获能提供微环境,间接支持精子成熟。各通道相互协作又互为制衡,构成了一张精密的调控网。近年来,电生理、结构生物学等领域的发展,学者们对CatSper复合体、sNHE双重门控机制、HVCN1“锌假说”等理论有了更深入的发现。有关于CatSper、sNHE及HVCN1等精子相关离子通道的研究也许能够广泛地应用于不育症基因筛查、男性不育的精准治疗、非激素类避孕等领域,为全球不孕不育难题开拓新的解决方向。

Abstract

The global prevalence of infertility has increased significantly, with male factors accounting for approximately 50% of cases. A primary etiology of male infertility involves abnormalities in sperm function and/or morphology; notably, spermatogenesis, maturation, and functional execution are highly dependent on ion channel proteins. In this review, we systematically summarize the ion channels directly or indirectly involved in spermatogenesis, maturation, and activation. We highlight the roles of key channel and transporter proteins-including CatSper, bicarbonate transporters (SLC4/SLC26), sodium-hydrogen exchangers (NHEs), and HVCN1-in mediating crucial processes such as intracellular alkalinization and Ca²⁺ influx. Furthermore, we outline channel proteins that indirectly participate in sperm development and maturation, such as aquaporins (AQP3/7/8/9), CFTR, and CLC-2. Together, these ion channels cooperate and counterbalance one another, establishing a sophisticated and precise regulatory network. In recent years, rapid advancements in electrophysiology and structural biology have provided deeper insights into the molecular architecture of the CatSper complex, the dual-gating mechanism of sNHE, and the “zinc hypothesis” of HVCN1. Looking ahead, insights into these sperm-associated ion channels hold great potential for broad clinical applications, ranging from genetic screening for infertility and precision therapeutics for male infertility to the development of non-hormonal male contraceptives, thereby offering novel paradigms to address global reproductive health challenges.

关键词

离子通道 / 男性生殖 / 精子发生 / 精子获能

Key words

ion channel / male reproduction / spermatogenesis / sperm capacitation

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基金资助

国家自然科学基金资助项目(82460290)