The acrosome reaction in sperm: A special type of regulated exocytosis

顶体反应的一个特点是精子头部的溶酶体相关顶体囊泡为其自身的胞吐作用提供Ca 2+。研究最近描述的内溶酶体钙释放通道的两个孔通道（TPC）家庭是否在哺乳动物精子中表达，以及其潜在的激活剂NAADP是否有助于顶体分泌，我们发现，两个独立的NAADP依赖性途径导致顶体胞吐，其中TPC 1被发现负责激活低亲和力级联。由于我们的研究结果也提供了TPC 2表达的证据，我们现在将研究TPC 2是否负责激活高亲和力NAADP信号通路，以及TPC 1和TPC 2的同时遗传缺失是否影响透明带诱导的顶体融合和动物的繁殖成功。然而，由于我们先前的研究也揭示了顶体IP 3 R和TPC之间可能的功能性串扰，我们还将研究TPC的共刺激是否以协同或相加的方式增强IP 3诱发的Ca 2+增加，以及我们最近在哺乳动物精子中鉴定的IP 3 R抑制剂伊尔比特，对顶体分泌有任何影响。在它们射出的精子到输卵管中的成熟卵子的长途旅行中，精子暴露在浓度逐渐变化的不同化合物中，这些化合物的识别能力与精子直接相关。卵母细胞与卵母细胞周围透明带相互作用的能力。然而，我们目前的知识，适当的化学感受器的蛋白质，识别pH值的变化，但也梯度的不同的糖，氨基酸或激素的分子身份仍然是初步的。在这种情况下，最近发现的异位表达的味觉受体是值得一提的，这在味蕾上的舌头是已知的检测广谱的化合物具有不同的化学性质。检查雄性生殖细胞中味觉受体的表达，我们发现形成功能性鲜味受体（Tas 1 R1/Tas 1 R3，L-谷氨酸单钠）的两个结合伴侣，以及耦合味觉转导级联的组分，如G蛋白α亚基Gustducin和阳离子通道TRPM 5，在从小鼠到人类的精子中表达。此外，使用Tas 1 R1缺陷小鼠品系的精子，检测到自发顶体反应率的显著升高。然而，Tas 1 R3、Gustducin和TRPM 5是否也影响顶体分泌尚不清楚，尽管已经证明Tas 1 R3和Gustducin两者的同时遗传缺失使得敲除雄性不育。因此，我们将系统地研究顶体反应效率与Tas 1 Rs，Gustducin和TRPM 5在小鼠以及人精子中的功能关系。

One special feature of the acrosome reaction is that the lysosome-related acrosomal vesicle in the sperm head supplies Ca2+ for its own exocytosis. Investigating whether the recently described endo-lysosomal Ca2+ release channels of the two pore channel (TPC) family are expressed in mammalian spermatozoa, and whether their potential activator NAADP contributes to acrosomal secretion we found that two independent NAADP-dependent pathways cause acrosomal exocytosis, where TPC1 was found to be responsible for activating the low affinity cascade. Since our results also provide evidence for an expression of TPC2, we will now examine whether TPC2 is responsible to activate the high affinity NAADP signaling pathway, and whether a simultaneous genetic deletion of TPC1 and TPC2 affects Zona pellucida induced fusion of the acrosome and breeding successful of the animals. However, since our previous study also uncovered a possible functional cross talk between the acrosomal IP3R and TPCs, we will also investigate whether a co-stimulation of TPCs enhances an IP3 evoked Ca2+ increase in a synergistic or in an additive manner, and whether IRBIT, an inhibitor of the IP3R, which we recently identified in mammalian spermatozoa, has any impact on acrosomal secretion.During their long distant journey of ejaculated sperm to the mature egg in the oviduct, sperm are exposed to progressively changing concentrations of different chemical compounds whose recognition capacity is directly linked to the sperm`s ability to interact with the Zona pellucida surrounding the oocyte. However, our current knowledge about the molecular identity of appropriate chemosensory receptor proteins which recognize changes in pH, but also gradients of different sugars, amino acids or hormones is still rudimental. In this context, the recent discovery of an ectopic expression of taste receptors is worth mentioning, which in taste buds on the tongue are known to detect a broad spectrum of compounds with different chemical properties. Examining the expression of taste receptors in male germ cells we found that the two binding partners, which form the functional umami receptor (Tas1R1/Tas1R3, Monosodium L-Glutamat), and components of the coupled taste transduction cascade, like the G protein alpha subunit Gustducin and the cation channel TRPM5 are expressed in sperm from mice to humans. In addition, using sperm of a Tas1R1 deficient mouse strain, a significant elevation of the spontaneous acrosome reaction rate was detected. However, whether Tas1R3, Gustducin and TRPM5 also affect acrosomal secretion, is not yet clear, although it has been demonstrated that a simultaneous genetic absence of both, Tas1R3 and Gustducin renders knock-out males sterile. Therefore, we will systematically examine the functional relationship between the efficiency of acrosome reaction and Tas1Rs, Gustducin and TRPM5 in mouse as well as in human sperm.