SOLUBLE ADENYLYL CYCLASE ACTIVITY IN MALE GERM CELLS

Summary

Principal Investigator: LONNY R contact LEVIN
Abstract: DESCRIPTION: (Adapted from the applicant's abstract) cAMP, a nearly universal signaling molecule, is synthesized from ATP by a broad family of adenylyl cyclases (AC). In mammals, there are two types of AC. One form spans the membrane and is encoded by a gene family consisting of nine related transmembrane ACs (tmAC). These are regulated by G proteins and other second messengers. The P.I. has recently identified a second type of mammalian AC, soluble AC (sAC) that is insensitive to the known modulators of tmACs and does not possess membrane spanning domains. tmAC and sAC appear to mediate opposite effects on cellular proliferation and are differentially modulated by pharmacological agents. sAC activity is directly regulated by bicarbonate ions. Since sAC is preferentially expressed in male germ cells and is the only known bicarbonate stimulated adenylyl cyclase in mammals, the investigators propose that it is an excellent candidate to play roles in aspects of sperm motility, capacitiation and the acrosome reaction. The proposed studies will determine the regulatory and enzymological profile of sAC and use pharmacological and genetic approaches to test the role of sAC in reproductive function. Long term plans include developing sAC as a potential target for pharmacological therapeutics affecting fertility.
Funding Period: 2001-02-15 - 2005-01-31
more information: NIH RePORT

Top Publications

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. pmc Somatic 'soluble' adenylyl cyclase isoforms are unaffected in Sacy tm1Lex/Sacy tm1Lex 'knockout' mice
    Jeanne Farrell
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA
    PLoS ONE 3:e3251. 2008

Scientific Experts

  • Carl F Nathan
  • Jochen Buck
  • Lonny R Levin
  • Margarita Kamenetsky
  • Martin Tresguerres
  • Kenneth C Hess
  • Sabine Middelhaufe
  • Clemens Steegborn
  • Jonathan H Zippin
  • Thomas R Kolodecik
  • Hyun B Choi
  • Jonathan Chen
  • Lavoisier S Ramos-Espiritu
  • Rebeca Acín-Pérez
  • Lavoisier S Ramos
  • Christine Schlicker
  • Jeanne Farrell
  • Carmen Beltrán
  • Andreas Schmid
  • Yanqiu Chen
  • Alexander M Stessin
  • James A Chaloupka
  • Karen Y Wu
  • Hyunsil Han
  • Ravi L Rungta
  • Ning Zhou
  • Jennifer Martinez
  • Chao Tai
  • James G McLarnon
  • Fred S Gorelick
  • Jae K Ryu
  • Edwin C Thrower
  • Brian A MacVicar
  • Christine A Shugrue
  • Martina Leipelt
  • Teresa A Milner
  • Grant R J Gordon
  • Eric Salazar
  • Giovanni Manfredi
  • Ken C Hess
  • Barbara Kachholz
  • Annika Rauch
  • Jonathan Hale Zippin
  • Lavoisier Ramos
  • Gregory E Conner
  • Gary Moy
  • Nevis Fregien
  • Gabor Horvath
  • Nathalie Schmid
  • Victor D Vacquier
  • Zoltan Sutto
  • Alberto Darszon
  • Marie Christine Nlend
  • Matthias Salathe
  • Ulrich Hengst
  • Erin M Bank
  • David R Huron
  • Samie R Jaffrey
  • Stewart A Bullock
  • Vadim Iourgenko
  • Becky Marquez
  • Kenneth Hess
  • Susan S Suarez
  • Alexander Stessin
  • Teri S Ord
  • Gregory S Kopf
  • Stuart B Moss
  • Olivia Lou
  • Narinder Gautam
  • Carmen J Williams
  • William A Muller
  • Edward Hyde
  • Catarina Miyamoto
  • Brian H Jones
  • Julia Roberts
  • Noah Nathan

Detail Information

Publications20

  1. 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...
  2. 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
    ....
  3. 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...
  4. 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...
  5. 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
    ....
  6. 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...
  7. 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...
  8. 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
    ....
  9. 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...
  10. pmc Somatic 'soluble' adenylyl cyclase isoforms are unaffected in Sacy tm1Lex/Sacy tm1Lex 'knockout' mice
    Jeanne Farrell
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA
    PLoS ONE 3:e3251. 2008
    ..The absence of any major somatic phenotype is inconsistent with the variety of somatic functions identified for sAC using pharmacological inhibitors and RNA interference...
  11. pmc Glucose and GLP-1 stimulate cAMP production via distinct adenylyl cyclases in INS-1E insulinoma cells
    Lavoisier S Ramos
    Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10065, USA
    J Gen Physiol 132:329-38. 2008
    ..These results demonstrate that sAC-generated and tmAC-generated cAMP define distinct signaling cascades...
  12. pmc Structure-based development of novel adenylyl cyclase inhibitors
    Christine Schlicker
    Department of Physiological Chemistry, Ruhr University Bochum, Universitatsstrasse 150, 44801 Bochum, Germany
    J Med Chem 51:4456-64. 2008
    ..Our results show that compounds exploiting the catechol estrogen binding site can produce potent, isoform discriminating AC inhibitors...
  13. pmc Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP
    Andreas Schmid
    Division of Pulmonary and Critical Care, University of Miami, Miami, FL 33136, USA
    J Gen Physiol 130:99-109. 2007
    ..Thus, sAC is localized to motile airway cilia and it contributes to the regulation of human airway CBF. In addition, CO(2)/HCO(3)(-) increases indeed reversibly stimulate intracellular cAMP production by sAC in intact cells...
  14. pmc Particulate and soluble adenylyl cyclases participate in the sperm acrosome reaction
    Carmen Beltrán
    Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Cuernavaca, Morelos CP 62250, Mexico
    Biochem Biophys Res Commun 358:1128-35. 2007
    ..Our findings employing selective inhibitors for each class of AC indicate that both sAC and tmACs participate in the sperm acrosome reaction...
  15. pmc Soluble adenylyl cyclase is required for netrin-1 signaling in nerve growth cones
    Karen Y Wu
    Department of Pharmacology, Weill Medical College, Cornell University, New York, New York 10021, USA
    Nat Neurosci 9:1257-64. 2006
    ..Taken together, these results indicate that netrin-1 signals through sAC-generated cAMP, and identify a fundamental role for sAC in axonal development...
  16. pmc Soluble adenylyl cyclase mediates nerve growth factor-induced activation of Rap1
    Alexander M Stessin
    Department of Pharmacology, and Tri institutional M D Ph D Program, Weill Medical College of Cornell University, New York, New York 10021, USA
    J Biol Chem 281:17253-8. 2006
    ..These results identify sAC as a mediator of NGF signaling and reveal the existence of distinct pathways leading to cAMP-dependent signal transduction...
  17. pmc The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for fertilization
    Kenneth C Hess
    Department of Pharmacology, Joan and Sanford Weill Medical College, Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA
    Dev Cell 9:249-59. 2005
    ..This inhibitor revealed that capacitation is defined by separable events: induction of protein tyrosine phosphorylation and motility are sAC dependent while acrosomal exocytosis is not dependent on sAC...
  18. pmc Autoinhibitory regulation of soluble adenylyl cyclase
    James A Chaloupka
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA
    Mol Reprod Dev 73:361-8. 2006
    ..Our results identify an additional regulatory mechanism specific to the sAC(fl) isoform...
  19. pmc Molecular details of cAMP generation in mammalian cells: a tale of two systems
    Margarita Kamenetsky
    Department of Pharmacology, Joan and Sanford I Weill Medical College of Cornell University, New York, NY 10021, USA
    J Mol Biol 362:623-39. 2006
    ..This comparison reveals the mechanisms underlying their different properties but also illustrates many unifying themes for these evolutionary related signaling enzymes...
  20. pmc Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils
    Hyunsil Han
    Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
    J Exp Med 202:353-61. 2005
    ..Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function...