Home LiteratureArticle Details
PMID: 16054031 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for fertilization.

Developmental cell ·Vol. 9 ·No. 2 ·2005-08-00 ·Pages 249-59

Hess KC, Jones BH, Marquez B, Chen Y, Ord TS, Kamenetsky M, Miyamoto C, Zippin JH, Kopf GS, Suarez SS, Levin LR, Williams CJ, Buck J, Moss SB

Abstract

Mammalian fertilization is dependent upon a series of bicarbonate-induced, cAMP-dependent processes sperm undergo as they "capacitate," i.e., acquire the ability to fertilize eggs. Male mice lacking the bicarbonate- and calcium-responsive soluble adenylyl cyclase (sAC), the predominant source of cAMP in male germ cells, are infertile, as the sperm are immotile. Membrane-permeable cAMP analogs are reported to rescue the motility defect, but we now show that these "rescued" null sperm were not hyperactive, displayed flagellar angulation, and remained unable to fertilize eggs in vitro. These deficits uncover a requirement for sAC during spermatogenesis and/or epididymal maturation and reveal limitations inherent in studying sAC function using knockout mice. To circumvent this restriction, we identified a specific sAC inhibitor that allowed temporal control over sAC activity. 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.

MeSH Terms
Acrosome/physiology Adenylyl Cyclase Inhibitors Adenylyl Cyclases/metabolism Animals Cyclic AMP/biosynthesis Exocytosis Fertilization/drug effects,physiology Male Mice Mice, Knockout Phosphorylation Signal Transduction/drug effects,physiology Solubility Sperm Capacitation/drug effects Sperm Motility Spermatozoa/drug effects,physiology Tyrosine/metabolism
Chemicals
Adenylyl Cyclase Inhibitors Tyrosine Cyclic AMP Adenylyl Cyclases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Hess Kenneth C
Department of Pharmacology, Joan and Sanford Weill Medical College, Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
Jones Brian H
Marquez Becky
Chen Yanqiu
Ord Teri S
Kamenetsky Margarita
Miyamoto Catarina
Zippin Jonathan H
Kopf Gregory S
Suarez Susan S
Levin Lonny R
Williams Carmen J
Buck Jochen
Moss Stuart B
References (55)
55 references, click to expand
  1. Regulation of human sperm capacitation by a cholesterol efflux-stimulated signal transduction pathway leading to protein kinase A-mediated up-regulation of protein tyrosine phosphorylation.
    Mol Hum Reprod. 1999 Nov;5(11):1017-26 PMID: 10541563
  2. Inactivation of the mouse adenylyl cyclase 3 gene disrupts male fertility and spermatozoon function.
    Mol Endocrinol. 2005 May;19(5):1277-90 PMID: 15705663
  3. Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor.
    Science. 2000 Jul 28;289(5479):625-8 PMID: 10915626
  4. Mouse sperm protein sp56 is a component of the acrosomal matrix.
    Biol Reprod. 2001 Jan;64(1):36-43 PMID: 11133656
  5. Functional relationships between capacitation-dependent cell signaling and compartmentalized metabolic pathways in murine spermatozoa.
    J Biol Chem. 2001 Mar 9;276(10):7630-6 PMID: 11115497
  6. Identification and functional analysis of splice variants of the germ cell soluble adenylyl cyclase.
    J Biol Chem. 2001 Aug 24;276(34):31698-708 PMID: 11423534
  7. Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa.
    Biol Reprod. 2002 Aug;67(2):423-30 PMID: 12135876
  8. Activation of protein kinase A during human sperm capacitation and acrosome reaction.
    J Androl. 2002 Sep-Oct;23(5):709-16 PMID: 12185106
  9. Hyperactivated motility of bull sperm is triggered at the axoneme by Ca2+ and not cAMP.
    Dev Biol. 2002 Oct 1;250(1):208-17 PMID: 12297107
  10. Porcine sperm capacitation and tyrosine kinase activity are dependent on bicarbonate and calcium but protein tyrosine phosphorylation is only associated with calcium.
    Biol Reprod. 2003 Jan;68(1):207-13 PMID: 12493715
  11. Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains.
    FASEB J. 2003 Jan;17(1):82-4 PMID: 12475901
  12. Phosphoproteome analysis of capacitated human sperm. Evidence of tyrosine phosphorylation of a kinase-anchoring protein 3 and valosin-containing protein/p97 during capacitation.
    J Biol Chem. 2003 Mar 28;278(13):11579-89 PMID: 12509440
  13. Kinetic properties of "soluble" adenylyl cyclase. Synergism between calcium and bicarbonate.
    J Biol Chem. 2003 May 2;278(18):15922-6 PMID: 12609998
  14. Evidence for multiple distinctly localized adenylyl cyclase isoforms in mammalian spermatozoa.
    Mol Reprod Dev. 2003 Oct;66(2):181-9 PMID: 12950106
  15. Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10676-81 PMID: 12958208
  16. Expression of the soluble adenylyl cyclase during rat spermatogenesis: evidence for cytoplasmic sites of cAMP production in germ cells.
    Dev Biol. 2004 Jan 1;265(1):196-206 PMID: 14697363
  17. Bovine sperm capacitation: assessment of phosphodiesterase activity and intracellular alkalinization on capacitation-associated protein tyrosine phosphorylation.
    Mol Reprod Dev. 2004 Apr;67(4):487-500 PMID: 14991741
  18. Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect.
    Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2993-8 PMID: 14976244
  19. Electron microscopic cytochemistry of adenylyl cyclase activity in mouse spermatozoa.
    J Histochem Cytochem. 2004 Jun;52(6):833-6 PMID: 15150292
  20. Different signaling pathways in bovine sperm regulate capacitation and hyperactivation.
    Biol Reprod. 2004 Jun;70(6):1626-33 PMID: 14766720
  21. Abnormal sperm in mice with targeted deletion of the act (activator of cAMP-responsive element modulator in testis) gene.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10620-5 PMID: 15247423
  22. Micropuncture studies of the electrochemical aspects of fluid and electrolyte transport in individual seminiferous tubules, the epididymis and the vas deferens in rats.
    J Physiol. 1971 Mar;213(3):557-70 PMID: 5551402
  23. Development of a Mn-2+-sensitive, "soluble" adenylate cyclase in rat testis.
    Proc Natl Acad Sci U S A. 1975 Mar;72(3):1097-101 PMID: 1055368
  24. Spermatogenic cells of the prepuberal mouse. Isolation and morphological characterization.
    J Cell Biol. 1977 Jul;74(1):68-85 PMID: 874003
  25. Dissociation of the mouse testis and characterization of isolated spermatogenic cells.
    J Histochem Cytochem. 1977 Jul;25(7):480-94 PMID: 893996
  26. Separation of soluble adenylate and guanylate cyclases from the mature rat testis.
    Biochim Biophys Acta. 1979 Apr 3;583(4):531-4 PMID: 34443
  27. Regulation of guinea pig sperm adenylate cyclase by calcium.
    Biol Reprod. 1979 Dec;21(5):1135-42 PMID: 117845
  28. Dibutyryl cyclic AMP decreases capacitation time in vitro in mouse spermatozoa.
    J Reprod Fertil. 1981 May;62(1):63-72 PMID: 6262510
  29. A requirement of bicarbonate for Ca2+-induced elevations of cyclic AMP in guinea pig spermatozoa.
    J Biol Chem. 1982 Aug 10;257(15):8980-4 PMID: 6284752
  30. Sodium bicarbonate in seminal plasma stimulates the motility of mammalian spermatozoa through direct activation of adenylate cyclase.
    J Biol Chem. 1985 Aug 15;260(17):9699-705 PMID: 2991260
  31. Development of activatable adenylate cyclase in the preimplantation mouse embryo and a role for cyclic AMP in blastocoel formation.
    Cell. 1986 Jul 4;46(1):95-103 PMID: 3013420
  32. Stimulation of partially purified adenylate cyclase from bull sperm by bicarbonate.
    FEBS Lett. 1987 Jun 22;218(1):148-52 PMID: 3036587
  33. Relationship between the M42 antigen of mouse sperm and the acrosome reaction induced by ZP3.
    Dev Biol. 1989 Mar;132(1):174-8 PMID: 2917692
  34. cAMP-dependent regulatory processes in the acquisition and control of sperm flagellar movement.
    Prog Clin Biol Res. 1988;267:335-55 PMID: 2853368
  35. Relationship between calcium, cyclic AMP, ATP, and intracellular pH and the capacity of hamster spermatozoa to express hyperactivated motility.
    Gamete Res. 1989 Feb;22(2):163-77 PMID: 2540081
  36. Bicarbonate dependence of cAMP accumulation induced by phorbol esters in hamster spermatozoa.
    Biochim Biophys Acta. 1990 Sep 1;1054(2):231-6 PMID: 2169311
  37. p95, the major phosphotyrosine-containing protein in mouse spermatozoa, is a hexokinase with unique properties.
    J Biol Chem. 1994 Feb 4;269(5):3810-7 PMID: 7508920
  38. Capacitation of mouse spermatozoa. I. Correlation between the capacitation state and protein tyrosine phosphorylation.
    Development. 1995 Apr;121(4):1129-37 PMID: 7743926
  39. Capacitation of mouse spermatozoa. II. Protein tyrosine phosphorylation and capacitation are regulated by a cAMP-dependent pathway.
    Development. 1995 Apr;121(4):1139-50 PMID: 7538069
  40. Truncation and alanine-scanning mutants of type I adenylyl cyclase.
    Biochemistry. 1995 Nov 7;34(44):14563-72 PMID: 7578062
  41. Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice.
    Nature. 1996 Mar 14;380(6570):159-62 PMID: 8600390
  42. Severe impairment of spermatogenesis in mice lacking the CREM gene.
    Nature. 1996 Mar 14;380(6570):162-5 PMID: 8600391
  43. Cyclic adenosine 3',5'monophosphate-dependent regulation of protein tyrosine phosphorylation in relation to human sperm capacitation and motility.
    Biol Reprod. 1996 Sep;55(3):684-92 PMID: 8862788
  44. Regulation of protein tyrosine phosphorylation in human sperm by a calcium/calmodulin-dependent mechanism: identification of A kinase anchor proteins as major substrates for tyrosine phosphorylation.
    Dev Biol. 1996 Nov 25;180(1):284-96 PMID: 8948591
  45. The olfactory adenylyl cyclase type 3 is expressed in male germ cells.
    FEBS Lett. 1998 Mar 13;424(3):216-20 PMID: 9539154
  46. The olfactory adenylyl cyclase III is expressed in rat germ cells during spermiogenesis.
    Endocrinology. 1998 May;139(5):2588-99 PMID: 9564875
  47. Coupling gene expression to cAMP signalling: role of CREB and CREM.
    Int J Biochem Cell Biol. 1998 Jan;30(1):27-38 PMID: 9597751
  48. Enhancement of motility and acrosome reaction in human spermatozoa: differential activation by type-specific phosphodiesterase inhibitors.
    Hum Reprod. 1998 May;13(5):1248-54 PMID: 9647555
  49. Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals.
    Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):79-84 PMID: 9874775
  50. Discrete regional distributions suggest diverse functional roles of calcium channel alpha1 subunits in sperm.
    Dev Biol. 1999 Mar 15;207(2):457-69 PMID: 10068476
  51. Real-time observation of acrosomal dispersal from mouse sperm using GFP as a marker protein.
    FEBS Lett. 1999 Apr 23;449(2-3):277-83 PMID: 10338148
  52. Roles of bicarbonate, cAMP, and protein tyrosine phosphorylation on capacitation and the spontaneous acrosome reaction of hamster sperm.
    Biol Reprod. 1999 Jul;61(1):76-84 PMID: 10377034
  53. Fertilizing capacity of spermatozoa deposited into the fallopian tubes.
    Nature. 1951 Oct 20;168(4277):697-8 PMID: 14882325
  54. The capacitation of the mammalian sperm.
    Nature. 1952 Aug 23;170(4321):326 PMID: 12993150
  55. Specific expression of soluble adenylyl cyclase in male germ cells.
    Mol Reprod Dev. 2000 May;56(1):6-11 PMID: 10737962
Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1534-5807
DOI
10.1016/j.devcel.2005.06.007
Published
2005-08-00
Pages
249-59
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC3082461
Subset
IM
Grants
NICHD NIH HHS · HD044740 · United States
NICHD NIH HHS · NIH HD42060 · United States
NICHD NIH HHS · HD38722 · United States
NICHD NIH HHS · R01 HD038722 · United States
NICHD NIH HHS · R01 HD044740 · United States
NICHD NIH HHS · F31 HD043693 · United States
NIGMS NIH HHS · R01 GM062328 · United States
NICHD NIH HHS · R01 HD038722-04 · United States
NICHD NIH HHS · R01 HD038722-02 · United States
NICHD NIH HHS · R01 HD059913-02 · United States
NICHD NIH HHS · R01 HD059913-01 · United States
NICHD NIH HHS · R01 HD038722-01A1 · United States
NICHD NIH HHS · R01 HD059913-03 · United States
NICHD NIH HHS · R01 HD038722-03 · United States
NICHD NIH HHS · R01 HD059913 · United States
NIGMS NIH HHS · GM62328 · United States
NICHD NIH HHS · 5 F31 HD43693 · United States
External Links
PubMed source DOI: 10.1016/j.devcel.2005.06.007 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2