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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (02))
Program Officer
Moss, Stuart B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
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
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
Chen, Jonathan; Levin, Lonny R; Buck, Jochen (2012) Role of soluble adenylyl cyclase in the heart. Am J Physiol Heart Circ Physiol 302:H538-43
Ramos-Espiritu, Lavoisier S; Hess, Kenneth C; Buck, Jochen et al. (2011) The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells. J Pharmacol Exp Ther 338:925-31
Buck, Jochen; Levin, Lonny R (2011) Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling. Sensors (Basel) 11:2112-28
Tresguerres, Martin; Levin, Lonny R; Buck, Jochen (2011) Intracellular cAMP signaling by soluble adenylyl cyclase. Kidney Int 79:1277-88

Showing the most recent 10 out of 12 publications