Crosstalk of Calcium and other pathways in capacitation

描述(申请人提供)：哺乳动物的精子不能在射精后立即使卵子受精。它们通过一个过程获得雌性生殖道的受精能力 这被称为获能。最初，获能的定义是以受精为终点。然而，各种证据表明，精子在获能过程中发生的功能变化不是一个事件，而是一个连续和伴随的过程的组合。这些过程与运动模式的变化(例如，过度激活)和准备进行激动剂刺激的顶体反应的精子有关。在分子水平上，获能与cAMP信号通路的激活、细胞内pH的升高、精子质膜电位的改变、酪氨酸磷酸化的增加以及细胞内钙离子浓度([Ca2+]i)的上调有关。特别是，钙离子在调节过度激活和AR中起着核心作用。然而，控制精子内[Ca~(2+)]i的分子机制还不是很清楚。支持这一建议的中心假设是，过度激活是cAMP和钙依赖的信号通路之间相互干扰的结果。这项建议的目的是了解在获能过程中钙离子和其他信号通路(如phi、cAMP的增加和Em的变化)是如何整合的。

DESCRIPTION (provided by applicant): Mammalian sperm are not able to fertilize eggs immediately after ejaculation. They acquire fertilization capacity in the female tract in a process known as capacitation. Initially, capacitation was defined using fertilization as an end-point. However, a variety of evidence suggests that the functional changes occurring in the sperm during capacitation are not one event, but a combination of sequential and concomitant processes. These processes are associated with changes in the motility pattern (e.g. hyperactivation) and with preparation of sperm to undergo an agonist-stimulated acrosome reaction. At the molecular level, capacitation is associated with the activation of a cAMP signaling pathway, increase in intracellular pH, changes in the sperm plasma membrane potential, increase in tyrosine phosphorylation and with up-regulation of intracellular Ca2+ concentration ([Ca2+]i). In particular Ca2+ plays central roles in the regulation of both hyperactivation and the AR. However, the molecular mechanisms that control [Ca2+]i in sperm are not well established. The central hypothesis underlying this proposal posits that hyperactivation is the consequence of crosstalk between cAMP and Ca2+-depending signaling pathways. The objective of this proposal is to understand how Ca2+ and other signaling pathways (e.g. increase in pHi, cAMP and changes in Em) integrate during capacitation.