Soluble adenylyl cyclase isoforms essential for male fertility

Summary

Principal Investigator: Lonny R Levin
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2009-06-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation
    Rebeca Acín-Pérez
    Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA
    Cell Metab 9:265-76. 2009
  2. pmc Activation of soluble adenylyl cyclase protects against secretagogue stimulated zymogen activation in rat pancreaic acinar cells
    Thomas R Kolodecik
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
    PLoS ONE 7:e41320. 2012
  3. pmc Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase
    Hyun B Choi
    Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada
    Neuron 75:1094-104. 2012
  4. pmc Neuronal expression of soluble adenylyl cyclase in the mammalian brain
    Jonathan Chen
    Tri Institutional MD PhD Program, 1300 York Ave, Weill Cornell Medical College, New York, NY 10065, USA
    Brain Res 1518:1-8. 2013
  5. pmc cAMP and mitochondria
    Federica Valsecchi
    Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA
    Physiology (Bethesda) 28:199-209. 2013
  6. pmc Pharmacological distinction between soluble and transmembrane adenylyl cyclases
    Jacob L Bitterman
    Department of Pharmacology, Weill Cornell Medical College, New York, New York
    J Pharmacol Exp Ther 347:589-98. 2013
  7. pmc CO2/HCO3(-)- and calcium-regulated soluble adenylyl cyclase as a physiological ATP sensor
    Jonathan H Zippin
    From the Departments of Pharmacology and
    J Biol Chem 288:33283-91. 2013
  8. pmc Compartmentalization of distinct cAMP signaling pathways in mammalian sperm
    Eva Wertheimer
    From the Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003
    J Biol Chem 288:35307-20. 2013
  9. pmc Thiol changes during epididymal maturation: a link to flagellar angulation in mouse spermatozoa?
    T W Ijiri
    Center for Research on Reproduction and Women s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Department of Molecular Biosciences, Kyoto Sangyo University, Kyoto, Japan
    Andrology 2:65-75. 2014
  10. pmc Identification of a haem domain in human soluble adenylate cyclase
    Sabine Middelhaufe
    Department of Physiological Chemistry, Ruhr University Bochum, Bochum, Germany
    Biosci Rep 32:491-9. 2012

Detail Information

Publications21

  1. pmc Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation
    Rebeca Acín-Pérez
    Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA
    Cell Metab 9:265-76. 2009
    ....
  2. pmc Activation of soluble adenylyl cyclase protects against secretagogue stimulated zymogen activation in rat pancreaic acinar cells
    Thomas R Kolodecik
    Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
    PLoS ONE 7:e41320. 2012
    ..These data suggest that activation of sAC in the pancreatic acinar cell has a protective effect and reduces the pathologic activation of proteases during pancreatitis...
  3. pmc Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase
    Hyun B Choi
    Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada
    Neuron 75:1094-104. 2012
    ..These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons...
  4. pmc Neuronal expression of soluble adenylyl cyclase in the mammalian brain
    Jonathan Chen
    Tri Institutional MD PhD Program, 1300 York Ave, Weill Cornell Medical College, New York, NY 10065, USA
    Brain Res 1518:1-8. 2013
    ....
  5. pmc cAMP and mitochondria
    Federica Valsecchi
    Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA
    Physiology (Bethesda) 28:199-209. 2013
    ..Here, we discuss the role of cAMP in regulating mitochondrial bioenergetics through protein phosphorylation and the evidence for soluble adenylyl cyclase as the source of cAMP inside mitochondria...
  6. pmc Pharmacological distinction between soluble and transmembrane adenylyl cyclases
    Jacob L Bitterman
    Department of Pharmacology, Weill Cornell Medical College, New York, New York
    J Pharmacol Exp Ther 347:589-98. 2013
    ..These tools provide a means to define the specific contributions of the different families of adenylyl cyclases in cells and tissues, which will further our understanding of cell signaling. ..
  7. pmc CO2/HCO3(-)- and calcium-regulated soluble adenylyl cyclase as a physiological ATP sensor
    Jonathan H Zippin
    From the Departments of Pharmacology and
    J Biol Chem 288:33283-91. 2013
    ..Glucose metabolism also elicits insulin secretion, and we further show that sAC is necessary for normal glucose-stimulated insulin secretion in vitro and in vivo. ..
  8. pmc Compartmentalization of distinct cAMP signaling pathways in mammalian sperm
    Eva Wertheimer
    From the Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003
    J Biol Chem 288:35307-20. 2013
    ..Altogether, these data suggest that cAMP pathways are compartmentalized in sperm, with Gs and tmAC in the head and Adcy10 and PKA in the flagellum. ..
  9. pmc Thiol changes during epididymal maturation: a link to flagellar angulation in mouse spermatozoa?
    T W Ijiri
    Center for Research on Reproduction and Women s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Department of Molecular Biosciences, Kyoto Sangyo University, Kyoto, Japan
    Andrology 2:65-75. 2014
    ..Together, these results suggest that thiol changes during epididymal maturation have a role in the stabilization of the sperm flagellum. ..
  10. pmc Identification of a haem domain in human soluble adenylate cyclase
    Sabine Middelhaufe
    Department of Physiological Chemistry, Ruhr University Bochum, Bochum, Germany
    Biosci Rep 32:491-9. 2012
    ....
  11. pmc Role of soluble adenylyl cyclase in the heart
    Jonathan Chen
    Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10065, USA
    Am J Physiol Heart Circ Physiol 302:H538-43. 2012
    ..The possibility of producing cAMP from a source distal to the plasma membrane provides a critical new building block for reconstructing the cellular signaling infrastructure...
  12. pmc Regulation of anterior chamber drainage by bicarbonate-sensitive soluble adenylyl cyclase in the ciliary body
    Yong S Lee
    Department of Ophthalmology and Vision Science, University of Arizona, Tucson, Arizona 85719, USA
    J Biol Chem 286:41353-8. 2011
    ....
  13. pmc Bicarbonate-sensing soluble adenylyl cyclase is an essential sensor for acid/base homeostasis
    Martin Tresguerres
    Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:442-7. 2010
    ..sAC orthologs are present throughout metazoans, and mammalian sAC is expressed in A/B regulatory organs, suggesting that systemic A/B sensing via sAC is widespread in the animal kingdom...
  14. pmc Soluble adenylyl cyclase defines a nuclear cAMP microdomain in keratinocyte hyperproliferative skin diseases
    Jonathan H Zippin
    Department of Dermatology, NYPH Weill Cornell Medical Center, New York, New York, USA
    J Invest Dermatol 130:1279-87. 2010
    ..Hence, sAC may play a role in the pathogenesis of certain hyperproliferative skin disorders via modulation of gene expression...
  15. pmc Modulation of NaCl absorption by [HCO(3)(-)] in the marine teleost intestine is mediated by soluble adenylyl cyclase
    Martin Tresguerres
    Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    Am J Physiol Regul Integr Comp Physiol 299:R62-71. 2010
    ..This mechanism putatively coordinates HCO(3)(-) secretion with NaCl and water absorption in toadfish intestine...
  16. pmc Physiological carbon dioxide, bicarbonate, and pH sensing
    Martin Tresguerres
    Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, USA
    Pflugers Arch 460:953-64. 2010
    ..Yet, the molecular sensors for CO₂/HCO₃⁻/pH remained unknown until recently. Here, we review recent progress in delineating molecular and cellular mechanisms for sensing CO₂, HCO₃⁻, and pH...
  17. pmc Intracellular cAMP signaling by soluble adenylyl cyclase
    Martin Tresguerres
    Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California, USA
    Kidney Int 79:1277-88. 2011
    ..In this review, we detail the known functions of sAC, and we reassess commonly held views of cAMP signaling inside cells...
  18. pmc Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling
    Jochen Buck
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Sensors (Basel) 11:2112-28. 2011
    ....
  19. pmc The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells
    Lavoisier S Ramos-Espiritu
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA
    J Pharmacol Exp Ther 338:925-31. 2011
    ..Although YC-1 has been used as a tool for investigating sGC and cGMP-mediated pathways, this study reveals cGMP-independent pharmacological actions of this compound...
  20. pmc A phosphodiesterase 2A isoform localized to mitochondria regulates respiration
    Rebeca Acín-Pérez
    Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065, USA
    J Biol Chem 286:30423-32. 2011
    ..Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation...
  21. pmc Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate
    Silke Kleinboelting
    Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
    Proc Natl Acad Sci U S A 111:3727-32. 2014
    ..Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3(-) sensing and a basis for targeting this system with drugs. ..

Research Grants30

  1. Genetic Basis of Oligozoospermia in Infertile Males
    Alexander N Yatsenko; Fiscal Year: 2013
    ..The long-term career goals of the applicant is to become an independent physician-scientist focused on studying genetic disorders that affect male reproductive system. ..
  2. BICARBONATE REGULATED ADENYLYL CYCLASE
    Lonny R Levin; Fiscal Year: 2013
    ....
  3. Phosphorylation Events During Sperm Capacitation
    PABLO EDUARDO VISCONTI; Fiscal Year: 2013
    ..Accomplishment of these goals will lead to novel insights in clinical diagnosis of male infertility and provide tools for evaluating pharmacological contraceptive targets. ..
  4. Developing Selective Inhibitors of GAPDHS and Sperm Glycolysis for Contraception
    DEBORAH A O'BRIEN; Fiscal Year: 2013
    ..The availability of better contraceptive options for men would facilitate global public health and family planning efforts. ..
  5. MRNA PROCESSING IN REPRODUCTION AND FERTILIZATION
    Clinton C MacDonald; Fiscal Year: 2013
    ..Using a variety of techniques, we want to learn the molecular causes of why sperm production fails in males missing the CSTF2T gene, to better understand how to assist these infertile couples. ..
  6. Molecular Mechanisms that Control Ca2+ Signaling in Human Spermatozoa
    Yuriy Kirichok; Fiscal Year: 2013
    ..The results will help in the development of new treatments for male infertility as well as new methods of male contraception. ..
  7. AMERICAN SOCIETY OF ANDROLOGY ANNUAL MEETING
    DONNA LEE VOGEL; Fiscal Year: 2013
    ..abstract_text> ..
  8. Origins and Biological Consequences of Human Infertility
    Linda C Giudice; Fiscal Year: 2013
    ..abstract_text> ..
  9. Spatio-temporal dynamics of GEF-GTPase networks
    KLAUS MICHAEL HAHN; Fiscal Year: 2013
    ..abstract_text> ..
  10. Intercellular networks and luminal acidification in the male reproductive tract
    Sylvie Breton; Fiscal Year: 2013
    ..Data generated here will provide novel insights into the male reproductive tract in particular, as well as the physiology of acid/base transporting epithelia in general. ..
  11. AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)
    Neil B Ruderman; Fiscal Year: 2013
    ..The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention...
  12. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  13. Developing Male Contraceptives by Targeting ANT4
    Naohiro Terada; Fiscal Year: 2013
    ..PUBLIC RELEVANCE: This study has the potential to identify lead compounds and to ultimately develop novel male contraceptives that selectively eliminate male meiotic spermatocytes without damaging other cell types in the body. ..
  14. The evolutionary and molecular mechanisms underlying sperm performance in an emer
    Heidi S Fisher; Fiscal Year: 2013
    ....
  15. Regulation of Spermatogenesis by X-linked miRNAs
    Wei Yan; Fiscal Year: 2013
    ..Data from the present study will contribute insight into the function of X-linked miRNAs in the control of sperm production and male fertility. ..