Sperm-specific Protein Kinase A Catalytic Subunit Calpha2 Orchestrates CAMP Signaling for Male Fertility

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Sep 2

PMID 15340140

Citations 105

Authors

Michael A Nolan

Donner F Babcock

Gunther Wennemuth

William Brown

Kimberly A Burton

G Stanley McKnight

Affiliations

Soon will be listed here.

Abstract

An unusual cAMP signaling system mediates many of the events that prepare spermatozoa to meet the egg. Its components include the atypical, bicarbonate-stimulated, sperm adenylyl cyclase and a cAMP-dependent protein kinase (PKA) with the unique catalytic subunit termed Calpha(2) or C(s). We generated mice that lack Calpha(2) to determine its importance in the events downstream of cAMP production. Male Calpha(2) null mice produce normal numbers of sperm that swim spontaneously in vitro. Thus, Calpha(2) has no required role in formation of a functional flagellum or the initiation of motility. In contrast, we find that Calpha(2) is required for bicarbonate to speed the flagellar beat and facilitate Ca(2+) entry channels. In addition, Calpha(2) is needed for the protein tyrosine phosphorylation that occurs late in the sequence of sperm maturation and for a negative feedback control of cAMP production, revealed here. Consistent with these specific defects in several important sperm functions, Calpha(2) null males are infertile despite normal mating behavior. These results define several crucial roles of PKA in sperm cell biology, bringing together both known and unique PKA-mediated events that are necessary for male fertility.

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References

Ren D, Navarro B, Perez G, Jackson A, Hsu S, Shi Q . A sperm ion channel required for sperm motility and male fertility. Nature. 2001; 413(6856):603-9. PMC: 8462998. DOI: 10.1038/35098027. View

Jaiswal B, Conti M . Identification and functional analysis of splice variants of the germ cell soluble adenylyl cyclase. J Biol Chem. 2001; 276(34):31698-708. DOI: 10.1074/jbc.M011698200. View

Visconti P, Westbrook V, Chertihin O, Demarco I, Sleight S, Diekman A . Novel signaling pathways involved in sperm acquisition of fertilizing capacity. J Reprod Immunol. 2001; 53(1-2):133-50. DOI: 10.1016/s0165-0378(01)00103-6. View

Michel J, Scott J . AKAP mediated signal transduction. Annu Rev Pharmacol Toxicol. 2002; 42:235-57. DOI: 10.1146/annurev.pharmtox.42.083101.135801. View

Skalhegg B, Huang Y, Su T, Idzerda R, McKnight G, Burton K . Mutation of the Calpha subunit of PKA leads to growth retardation and sperm dysfunction. Mol Endocrinol. 2002; 16(3):630-9. DOI: 10.1210/mend.16.3.0793. View

Wennemuth G, Carlson A, Harper A, Babcock D . Bicarbonate actions on flagellar and Ca2+ -channel responses: initial events in sperm activation. Development. 2003; 130(7):1317-26. DOI: 10.1242/dev.00353. View

Ficarro S, Chertihin O, Westbrook V, White F, Jayes F, Kalab P . 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; 278(13):11579-89. DOI: 10.1074/jbc.M202325200. View

Suarez S, Ho H . Hyperactivation of mammalian sperm. Cell Mol Biol (Noisy-le-grand). 2003; 49(3):351-6. View

Jaiswal B, Conti M . Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa. Proc Natl Acad Sci U S A. 2003; 100(19):10676-81. PMC: 196863. DOI: 10.1073/pnas.1831008100. View

10.

Carlson A, Westenbroek R, Quill T, Ren D, Clapham D, Hille B . CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm. Proc Natl Acad Sci U S A. 2003; 100(25):14864-8. PMC: 299831. DOI: 10.1073/pnas.2536658100. View

11.

Quill T, Sugden S, Rossi K, Doolittle L, Hammer R, Garbers D . Hyperactivated sperm motility driven by CatSper2 is required for fertilization. Proc Natl Acad Sci U S A. 2003; 100(25):14869-74. PMC: 299835. DOI: 10.1073/pnas.2136654100. View

12.

Tasken K, Aandahl E . Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev. 2004; 84(1):137-67. DOI: 10.1152/physrev.00021.2003. View

13.

Harrison R . Rapid PKA-catalysed phosphorylation of boar sperm proteins induced by the capacitating agent bicarbonate. Mol Reprod Dev. 2004; 67(3):337-52. DOI: 10.1002/mrd.20028. View

14.

Esposito G, Jaiswal B, Xie F, Krajnc-Franken M, Robben T, Strik A . Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect. Proc Natl Acad Sci U S A. 2004; 101(9):2993-8. PMC: 365733. DOI: 10.1073/pnas.0400050101. View

15.

Lobley A, Pierron V, Reynolds L, Allen L, Michalovich D . Identification of human and mouse CatSper3 and CatSper4 genes: characterisation of a common interaction domain and evidence for expression in testis. Reprod Biol Endocrinol. 2003; 1:53. PMC: 184451. DOI: 10.1186/1477-7827-1-53. View

16.

Martins T, Mumby M, Beavo J . Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J Biol Chem. 1982; 257(4):1973-9. View

17.

Okamura N, Tajima Y, Soejima A, Masuda H, Sugita Y . Sodium bicarbonate in seminal plasma stimulates the motility of mammalian spermatozoa through direct activation of adenylate cyclase. J Biol Chem. 1985; 260(17):9699-705. View

18.

Macphee C, Reifsnyder D, Moore T, Lerea K, Beavo J . Phosphorylation results in activation of a cAMP phosphodiesterase in human platelets. J Biol Chem. 1988; 263(21):10353-8. View

19.

Yanagimachi R . Sperm capacitation and gamete interaction. J Reprod Fertil Suppl. 1989; 38:27-33. View

20.

Boatman D, Robbins R . Bicarbonate: carbon-dioxide regulation of sperm capacitation, hyperactivated motility, and acrosome reactions. Biol Reprod. 1991; 44(5):806-13. DOI: 10.1095/biolreprod44.5.806. View