MECHANISMS OF SIGNAL TRANSDUCTION IN SPERMATOZOA

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Mammalian sperm display numerous cellular changes that accompany both the acquisition of the fertilization-competent state and during the process of fertilization itself. Epididymal maturation of sperm is accompanied by the acquisition of progressive motility and the ability to undergo capacitation, a poorly understood maturational event required for successful fertilization. Ejaculated sperm undergo capacitation in the female reproductive tract, an event which is associated with changes in motility and the acquisition of the competence of the sperm to undergo acrosomal exocytosis in response to binding to the zona pellucida, the egg's extracellular matrix. All of these events - capacitation, motility, and acrosomal exocytosis- appear to be under control of both classical and unique intracellular signaling events that are modulated at the level of the plasma membrane via specific receptors/acceptor proteins and/or changes in plasma membrane properties. In this proposal, several unique aspects of the signal transduction events that may ultimately lead to capacitation, changes in motility and acrosomal exocytosis will be examined. One aim of this proposal will be to identify and characterize, by biochemical and molecular approaches, the tyrosine kinase(s) and/or phosphoprotein phosphatase(s) that are uniquely regulated in mouse sperm by cAMP/protein kinase A. A second aim will be to identify and characterize those proteins in the mouse sperm whose phosphorylation on tyrosine residues is stimulated by cAMP/protein kinase A, since these proteins may be involved in the capacitation process. A third aim will be to characterize and clone the cDNA encoding the sperm adenylyl cyclase, an enzyme that has unique properties in sperm and appears to be a central regulatory effector of capacitation, motility and the acrosome reaction. The final aim will be to determine the mechanism by which protein tyrosine phosphorylation is regulated by cAMP/protein kinase A during the capacitation process, since the crosstalk between protein kinase A and tyrosine kinase signaling pathways at this level is unique to sperm. Results of these studies focus on the molecular basis of signaling processes leading to the development of the fertilization- competent state, and will translate directly to the clinical setting of assisted reproductive technologies. Moreover, these studies will address fundamental questions in cell biology, namely, plasma membrane dynamics, receptor-effector coupling, and intracellular signal transduction crosstalk.