The ubiquitous second messenger, cAMP, plays multiple roles in male germ cells critical for mammalian fertilization. The major source of cAMP in sperm is the bicarbonate and calcium regulated soluble adenylyl cyclase (sAC). In testis, alternative splicing produces two isoforms, sACt and sACfl, and their deletion (in Sacytm1Lex knockout mice) or inhibition (by small molecule, sAC-specific inhibitor) blocks sperm motility, capacitation, and in vitro fertilization. Since both sACt and sACfl are removed in the Sacytm1Lex knockout and inhibited by the small molecule inhibitor, their individual contributions to the multiple sAC-derived cAMP-dependent processes in sperm remains unclear. In this application, we propose immunological, biochemical, and genetic experiments to determine whether there is a functional necessity for multiple sAC splice variants and to distinguish their individual roles in testis and male germ cells. These studies may justify sAC to be target for contraceptive intervention. The studies proposed here may reveal unique aspects to the regulation of sperm cAMP signal transduction which could define a new target for contraceptive intervention.

Public Health Relevance

The studies proposed here may reveal unique aspects to the regulation of sperm cAMP signal transduction which could define a new target for contraceptive intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD059913-04
Application #
8286245
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (02))
Program Officer
Moss, Stuart B
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$333,282
Indirect Cost
$136,074
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Navarrete, Felipe A; Alvau, Antonio; Lee, Hoi Chang et al. (2016) Transient exposure to calcium ionophore enables in vitro fertilization in sterile mouse models. Sci Rep 6:33589
Levin, Lonny R; Buck, Jochen (2015) Physiological roles of acid-base sensors. Annu Rev Physiol 77:347-62
Kleinboelting, Silke; Diaz, Ana; Moniot, Sebastien et al. (2014) Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate. Proc Natl Acad Sci U S A 111:3727-32
Hess, Kenneth C; Liu, Jingjing; Manfredi, Giovanni et al. (2014) A mitochondrial CO2-adenylyl cyclase-cAMP signalosome controls yeast normoxic cytochrome c oxidase activity. FASEB J 28:4369-80
Ijiri, T W; Vadnais, M L; Huang, A P et al. (2014) Thiol changes during epididymal maturation: a link to flagellar angulation in mouse spermatozoa? Andrology 2:65-75
Bitterman, Jacob L; Ramos-Espiritu, Lavoisier; Diaz, Ana et al. (2013) Pharmacological distinction between soluble and transmembrane adenylyl cyclases. J Pharmacol Exp Ther 347:589-98
Chen, Jonathan; Martinez, Jennifer; Milner, Teresa A et al. (2013) Neuronal expression of soluble adenylyl cyclase in the mammalian brain. Brain Res 1518:1-8
Wertheimer, Eva; Krapf, Dario; de la Vega-Beltran, José L et al. (2013) Compartmentalization of distinct cAMP signaling pathways in mammalian sperm. J Biol Chem 288:35307-20
Valsecchi, Federica; Ramos-Espiritu, Lavoisier S; Buck, Jochen et al. (2013) cAMP and mitochondria. Physiology (Bethesda) 28:199-209
Zippin, Jonathan H; Chen, Yanqiu; Straub, Susanne G et al. (2013) CO2/HCO3(-)- and calcium-regulated soluble adenylyl cyclase as a physiological ATP sensor. J Biol Chem 288:33283-91

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