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.
Difficulties in earlier efforts to fertilize mammalian eggs in vitro were due mainly to a lack of comprehension of sperm physiology. This proposal is aimed to understand the molecular basis of sperm capacitation with emphasis in the regulation of the crosstalk between Ca2+ homeostasis and other signaling pathways in sperm. Accomplishment of these goals will provide tools for improving current Assisted Reproductive Technology (ART) methods and to identify novel contraceptive targets.
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