Phosphatidylinositol 3-kinase inhibition enhances human sperm motility

Luconi, Michaela; Marra, Fabio; Gandini, L.; Filimberti, E.; Lenzi, Andrea; Forti, Gianni; Baldi, Elisabetta

doi:10.1093/humrep/16.9.1931

Cited by 57 publications

(56 citation statements)

References 28 publications

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“…Our results show no effect of PI3-K inhibition in the percentage of progressively motile spermatozoa, and this differs from human studies in which the inhibition of PI3-K leads to an increase in the percentage of progressively motile spermatozoa (Luconi et al 2001, du Plessis et al 2004. This fact may be due, at least partially, to a more abaxial insertion of the boar sperm flagellum leading the spermatozoa of this species to a less linear pattern of motility (Briz et al 1995).…”

Section: Discussioncontrasting

confidence: 91%

“…Recent results show an important role for PI3-K in human and hamster sperm motility (Luconi et al 2001, NagDas et al 2002, du Plessis et al 2004. However, the effect of the inhibition of PI3-K is different depending on the species under study; inhibition of this kinase triggers an increase in human sperm motility, including hyperactivation (Luconi et al 2001, du Plessis et al 2004, whereas its inhibition decreases the hyperactivation during capacitation of hamster sperm motility (NagDas et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, there is increasing evidence suggesting a role for different kinases and phosphatases regulating sperm motility (Tash & Bracho 1994, Vijayaraghavan et al 2000, Luconi et al 2001, NagDas et al 2002. Recently, the presence of the phosphatidylinositol 3-kinase (PI3-K) has been demonstrated in mouse, hamster and human spermatozoa (Feng et al 1998, NagDas et al 2002.…”

Section: Introductionmentioning

confidence: 99%

“…PI3-K is widely expressed in somatic cells and plays an important role in mitogenic signaling and cell survival, cytoskeletal remodeling, metabolic control and vesicular trafficking (Wymann & Pirola 1998, Anderson & Jackson 2003. In human spermatozoa, inhibition of PI3-K with two structurally unrelated inhibitors, LY294002 and wortmannin, suggests a negative role for PI3-K in the regulation of the motility process (Luconi et al 2001, NagDas et al 2002, du Plessis et al 2004. Moreover, inhibition of PI3-K results in an increase in intracellular cAMP levels and in tyrosine phosphorylation of the PKAanchoring protein, AKAP3 in human sperm, which finally results in stimulation of the PKA binding to AKAP3 in sperm tails through the regulatory subunit RIIb .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of phosphatidylinositol 3-kinase modifies boar sperm motion parameters

Aparicio¹,

Gil²,

García-Herreros³

et al. 2005

Reproduction

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Motility is the most widely used indicator of sperm quality. Besides modulation by the cAMP pathway little is known regarding the intracellular pathways that regulate boar sperm motility. Recently the role of phosphatidylinositol 3-kinase (PI3-K) in the regulation of human sperm motility has been described. Therefore, the aim of this study was to investigate the role of PI3-K in boar sperm kinematics by using the specific PI3-K inhibitor, LY294002. Boar sperm was incubated up to 1 h in non-capacitating medium in the presence or absence of the cAMP analog, 8Br-cAMP or the PI3-K inhibitor, LY294002 or both. Boar sperm incubated in capacitating medium was treated in the presence or absence of LY294002. First, we have clearly identified that PI3-K is present in whole lysates of boar spermatozoa. Inhibition of PI3-K significantly increased boar sperm straight-line velocity, circular velocity and average velocity without an effect on the percentage of progressively motile spermatozoa in both media. Inhibition of PI3-K induced the same effects on boar sperm velocities as activation of the cAMP/protein kinase A (PKA) pathway and treatment with the PI3-K inhibitor, LY294002 had neither summatory nor synergic effects on boar sperm motion parameters when treated simultaneously with the cAMP analog 8Br-cAMP. Our data suggest that PI3-K plays a negative role, regulating boar sperm motion parameters through a possible inhibition of the cAMP/PKA activating pathway, and since some Computer Aided Sperm Analysis (CASA)-derived parameters have been related to field fertility our results point to the possibility of modulating sperm motile quality by modifying the PI3-K cellular pathway.

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Section: Discussioncontrasting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of phosphatidylinositol 3-kinase modifies boar sperm motion parameters

Aparicio¹,

Gil²,

García-Herreros³

et al. 2005

Reproduction

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“…In support of this hypothesis, Luconi and colleges have recently demonstrated that the inhibition of PI3K in human sperm increases cAMP levels and the subsequent phosphorylation of AKAP3 and recruitment of PKA in sperm tails . Functionally, this leads to an increase in the number of sperm displaying hyperactivated motility and enhanced zona pellucida binding (Du Plessis et al, 2004;Luconi et al, 2001). Further, PTPs have been demonstrated in sperm and have been shown to be involved in the tyrosine phosphorylation, dephosphorylation, and re-phosphorylation of a hamster sperm protein implicated in the regulation of hyperactivation (Si, 1999;Si and Okuno, 1999).…”

Section: Discussionmentioning

confidence: 99%

FGFR-1 signaling is involved in spermiogenesis and sperm capacitation

Cotton

Gibbs

Sanchez-Partida

et al. 2006

Journal of Cell Science

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Cloning of the fibroblast growth factor receptor (FGFR) adaptor Snt-2 cDNA and the identification of FGFR-1 protein in association with sperm tails, suggested that FGFR-1 signaling was involved in either sperm tail development or function. This hypothesis was tested by the creation of transgenic mice that specifically expressed a dominant-negative variant of FGFR-1 in male haploid germ cells. Mating of transgenic mice showed a significant reduction in pups per litter compared with wild-type littermates. Further analysis demonstrated that this subfertility was driven by a combination of reduced daily sperm output and a severely compromised ability of those sperm that were produced to undergo capacitation prior to fertilization. An analysis of key signal transduction proteins indicated that FGFR-1 is functional on wild-type sperm and probably signals via the phosphatidylinositol 3-kinase pathway. FGFR-1 activation also resulted in the downstream suppression of mitogen activated protein kinase signaling. These data demonstrate the FGFR-1 is required for quantitatively and qualitatively normal spermatogenesis and has a key role in the regulation of the global tyrosine phosphorylation events associated with sperm capacitation.

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Inhibitors of Phosphoinositide 3‐Kinase, LY294002 and Wortmannin, Affect Sperm Capacitation and Associated Phosphorylation of Proteins Differently: Ca²⁺‐Dependent Divergences

Nauc

Lamirande

Leclerc

et al. 2004

Journal of Andrology

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Sperm capacitation is regulated by multiple pathways that also control sperm motility and tyrosine (Tyr) phosphorylation of several sperm proteins. Among the reported pathways, phosphoinositide 3-kinase (PI3K) signaling and its role in modulating sperm postejaculatory changes and motility remain elusive. It was shown that wortmannin, a selective inhibitor of PI3K, prevents human sperm acrosome reaction. Using LY294002 (2-(4-morphlinyl)-8-phenyl-4H-1-benzopyran-4-one), another chemically different inhibitor of PI3K, it was suggested that this enzyme inhibits human sperm motility. In this study, we used the 2 known inhibitors of PI3K to investigate their effect on sperm capacitation and associated protein phosphorylation events. Our data show that sperm incubated with LY294002 undergo capacitation and increased Tyr phosphorylation of specific sperm proteins in a manner similar to that promoted by the capacitation inducer fetal cord serum ultrafiltrate (FCSu), as well as double phosphorylation of the threonine (Thr)-glutamine (Glu)-Tyr motif. Under similar conditions, wortmannin did not affect these sperm functions on its own, although it did prevent the effect induced by FCSu. Consistently, wortmannin decreased the phospho (P)-Tyr content of sperm proteins and prevented the phosphorylation of their Thr-Glu-Tyr motif. We also show by means of immunoblotting and cell fractionation experiments the presence of PI3K and its downstream effector Akt (protein kinase B) at the membrane level, as well as sperm heads and flagella. Our data show that human spermatozoa contain a consensus motif usually phosphorylated by Akt and that its P-serine (Ser)/Thr content is increased by both LY294002 and FCSu, while it is decreased by wortmannin. In addition, the 2 inhibitors differently affected the intracellular calcium concentration, [Ca(2+)](i). While LY294002 increased [Ca(2+)](i), wortmannin did not affect its content and did not prevent the LY294002 effect. Thus, we propose that the LY294002-promoted increase in [Ca(2+)](i) operates independently of PI3K. In conclusion, we suggest that special care be taken when using LY294002 to investigate the role that PI3K plays in a cellular phenomenon.

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Phosphatidylinositol 3-kinase inhibition enhances human sperm motility

Abstract: Our results suggest a negative role for PI3K in the development and maintenance of sperm motility and suggest a possible use of PI3K inhibitors to enhance motility in cases of asthenozoospermia.

Cited by 57 publications

References 28 publications

Inhibition of phosphatidylinositol 3-kinase modifies boar sperm motion parameters

Inhibition of phosphatidylinositol 3-kinase modifies boar sperm motion parameters

FGFR-1 signaling is involved in spermiogenesis and sperm capacitation

Inhibitors of Phosphoinositide 3‐Kinase, LY294002 and Wortmannin, Affect Sperm Capacitation and Associated Phosphorylation of Proteins Differently: Ca²⁺‐Dependent Divergences

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Phosphatidylinositol 3-kinase inhibition enhances human sperm motility

Abstract: Our results suggest a negative role for PI3K in the development and maintenance of sperm motility and suggest a possible use of PI3K inhibitors to enhance motility in cases of asthenozoospermia.

Cited by 57 publications

References 28 publications

Inhibition of phosphatidylinositol 3-kinase modifies boar sperm motion parameters

Inhibition of phosphatidylinositol 3-kinase modifies boar sperm motion parameters

FGFR-1 signaling is involved in spermiogenesis and sperm capacitation

Inhibitors of Phosphoinositide 3‐Kinase, LY294002 and Wortmannin, Affect Sperm Capacitation and Associated Phosphorylation of Proteins Differently: Ca2+‐Dependent Divergences

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Inhibitors of Phosphoinositide 3‐Kinase, LY294002 and Wortmannin, Affect Sperm Capacitation and Associated Phosphorylation of Proteins Differently: Ca²⁺‐Dependent Divergences