Quill Timothy A, Sugden Sarah A, Rossi Kristen L, Doolittle Lynda K, Hammer Robert E, Garbers David L
Cecil H. and Ida Green Center for Reproductive Biology Sciences, Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9051, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14869-74. doi: 10.1073/pnas.2136654100. Epub 2003 Dec 1.
Elevations of sperm Ca2+ seem to be responsible for an asymmetric form of motility called hyperactivation, which is first seen near the time of fertilization. The mechanism by which intracellular Ca2+ concentrations increase remains unknown despite considerable investigation. Although several prototypical voltage-gated calcium channels are present in spermatozoa, they are not essential for motility. Furthermore, the forward velocity and percentage of motility of spermatozoa are associated with infertility, but their importance relative to hyperactivation also remains unknown. We show here that disruption of the gene for a recently described sperm-specific voltage-gated cation channel, CatSper2, fails to significantly alter sperm production, protein tyrosine phosphorylation that is associated with capacitation, induction of the acrosome reaction, forward velocity, or percentage of motility, yet CatSper2-/- males are completely infertile. The defect that we identify in the null sperm cells is a failure to acquire hyperactivated motility, which seems to render spermatozoa incapable of generating the "power" needed for penetration of the extracellular matrix of the egg. A loss of power is suggested also by experiments in which the viscosity of the medium was increased after incubation of spermatozoa in normal capacitating conditions. In high-viscosity medium, CatSper2-null spermatozoa lost the ability to swim forward, whereas wild-type cells continued to move forward. Thus, CatSper2 is responsible for driving hyperactivated motility, and, even with typical sperm forward velocities, fertilization is not possible in the absence of this highly active form of motility.
精子钙离子浓度的升高似乎是一种名为超活化的不对称运动形式的原因，这种运动形式最早在受精时出现。尽管进行了大量研究，但细胞内钙离子浓度升高的机制仍然未知。虽然精子中存在几种典型的电压门控钙通道，但它们对运动并非必不可少。此外，精子的前进速度和运动百分比与不育有关，但其相对于超活化的重要性也仍然未知。我们在此表明，最近描述的精子特异性电压门控阳离子通道CatSper2的基因破坏，并未显著改变精子产生、与获能相关的蛋白质酪氨酸磷酸化、顶体反应的诱导、前进速度或运动百分比，但CatSper2基因敲除雄性完全不育。我们在缺失精子细胞中发现的缺陷是无法获得超活化运动，这似乎使精子无法产生穿透卵子细胞外基质所需的“动力”。在正常获能条件下孵育精子后增加培养基粘度的实验也表明动力丧失。在高粘度培养基中，CatSper2基因敲除的精子失去了向前游动的能力，而野生型细胞继续向前移动。因此，CatSper2负责驱动超活化运动，并且即使精子具有典型的前进速度，在没有这种高活性运动形式的情况下受精也是不可能的。
