It is well recognized that cAMP has important and multiple regulatory roles in sperm development. It also is crucial for the acquisition of sperm motility and competence in fertilization. Despite this knowledge, relatively little progress has been made in translating this understanding into clinical agents that might target cAMP for the development of contraceptive or fertility agents. Several reasons for this are apparent. Perhaps most importantly, it has proven difficult to identify targets that are relatively specific to the testis that might be expected to alter cyclic nucleotide metabolism or function selectively in this tissue. The fact that this second messenger system is ubiquitously used to regulate many systems in the body has proven a hindrance. Recently, two major advances have encouraged us to re-explore this option. First, a bicarbonate sensitive, """"""""sperm specific"""""""" adenylyl cyclase has been identified and characterized. This may provide the opportunity to develop both agonists and antagonists that will target sperm with relatively high selectivity. The second advance, which is the focus of this application, relates to the other side of the cyclic AMP equation, the cyclic nucleotide phosphodiesterases (PDEs) that degrade cAMP. Recently, we have identified three new phosphodiesterases that will hydrolyze cAMP, PDE8, PDE10, and PDE11, by using bioinformatic techniques. Two of these new ones, PDE8 and PDE11 are highly expressed in the testis and at least one of them, PDE8A, is expressed in developing sperm. In addition, earlier data show that other isozymes of PDE including several PDE1s, and PDE4s are also present in the testis. It seems likely that by pharmacological manipulation of one or more of the PDEs expressed in testis, perhaps along with the sperm specific adenylyl cyclase inhibitors or activators, that selective alteration in sperm function can be achieved. This hypothesis will first require a fuller understanding of the functions and roles of these enzymes in sperm development and function. This is the focus of this application.
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