Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality

Almog, Tal; Lazar, Shlomi; Reiss, Nachum; Etkovitz, Nir; Milch, Eyal; Rahamim, Nir; Dobkin-Bekman, Masha; Rotem, Ronit; Kalina, Moshe; Ramon, Jacob; Raziel, Arieh; Brietbart, Haim; Seger, Rony; Naor, Zvi

doi:10.1074/jbc.m710492200

Cited by 110 publications

(135 citation statements)

References 56 publications

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“…Almog et al (37) found prominent ERK1/2 immunoreactivity in the human sperm flagellum and showed that stimulation with OAG promoted phosphorylation of ERK1/2 and produced modest increases in motility. De Lamirande and Gagnon (38) also found that a transient rise in ERK1/2 activity during capacitating incubations of human sperm.…”

Section: Discussionmentioning

confidence: 99%

Testicular Expression of Adora3i2 in Adora3 Knockout Mice Reveals a Role of Mouse A3Ri2 and Human A3Ri3 Adenosine Receptors in Sperm*

Burnett¹,

Blais²,

Unadkat

et al. 2010

Journal of Biological Chemistry

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Adenosine is a candidate modulator of sperm motility in the female reproductive tract that increases sperm flagellar beat frequency in vitro. Past work suggested that this acceleration may involve equilibrative (ENT) and concentrative (CNT) nucleoside transporters. Here we show that Slc29a1 (ENT-1) is the predominant nucleoside transporter expressed in the mouse testis. Unexpectedly, the beat of Slc29a1-null sperm still accelerates in response to 2-chloro-2-deoxyadenosine (Cl-dAdo). The only known roles of sperm are to reach the egg and deliver its genetic payload and to initiate early signaling events in the zygote. Although the list is short, the tasks are complex, and the sperm requires numerous specialized components to accomplish these goals. Our recent work has focused on how the sperm applies its specialized components to control swimming behavior. We have combined biophysical methods with a genetic approach, using sperm from null-mutant (knock-out) mice that carry targeted disruptions of the genes for several of the components of the signaling pathways that operate in the sperm flagellum. This approach has provided definitive evidence for required roles of the unique CatSper ion channel proteins (1-7), for the atypical sperm adenylyl cyclase SACY 2

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Section: Discussionmentioning

confidence: 99%

Testicular Expression of Adora3i2 in Adora3 Knockout Mice Reveals a Role of Mouse A3Ri2 and Human A3Ri3 Adenosine Receptors in Sperm*

Burnett¹,

Blais²,

Unadkat

et al. 2010

Journal of Biological Chemistry

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“…by Hofmann (2004)). In spermatozoa, PKC was found to participate in sperm capacitation, acrosome reaction, and motility (Breitbart et al 1992, Breitbart & Naor 1999, Cohen et al 2004, Almog et al 2008.…”

Section: Cmentioning

confidence: 99%

PKA and CaMKII mediate PI3K activation in bovine sperm by inhibition of the PKC/PP1 cascade

Rotfeld¹,

Hillman²,

Ickowicz³

et al. 2014

Reproduction

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To enable fertilization, spermatozoa must undergo several biochemical processes in the female reproductive tract, collectively called capacitation. These processes involve protein kinase A (PKA)-dependent protein tyrosine phosphorylation including phosphatidylinositol-3-kinase (PI3K). It is not known how PKA, a serine/threonine (S/T) kinase, mediates tyrosine phosphorylation of proteins. We recently showed that inhibition of S/T phosphatase 1 (PP1) causes a significant increase in phospho-PI3K. In this study, we propose a mechanism by which PKA and PP1 mediate an increase in PI3K tyrosine phosphorylation and implicate calmodulin-dependent kinase II (CaMKII) in this process. Inhibition of sperm PP1 or PKC, stimulated CaMKII phosphorylation/activation, and inhibition of PKC enhanced PP1 phosphorylation/inactivation. Inhibition of CaMKII, using KN-93, caused significant reduction in phospho-PP1, indicating its activation. Moreover, KN-93 prevented the dephosphorylation/inactivation of PKC. We therefore suggest that CaMKII inhibits PKC, leading to PP1 inhibition and the reciprocal auto-activation of CaMKII. Thus, CaMKII can regulate its own activation by inhibiting the PKC/PP1 cascade. Inhibition of Src family kinases (SFK) caused significant inhibition of CaMKII and PP1 phosphorylation, suggesting that SFK activity results in PP1 inhibition and CaMKII activation. Activation of sperm PKA by 8Br-cAMP revealed an increase in phosphoCaMKII, which was inhibited by PKA inhibitor. Tyrosine phosphorylation of PI3K was stimulated by 8Br-cAMP and by PKC or PP1 inhibition and was abrogated by CaMKII inhibition. Furthermore, phosphorylation/activation of the tyrosine kinase Pyk2 was enhanced by PP1 inhibition, and this activation is blocked by CaMKII inhibition. Thus, PKA activates Src, which inhibits PP1, leading to CaMKII and Pyk2 activation, resulting in PI3K tyrosine phosphorylation/activation.

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“…In an in vivo study in rats, Jia et al (2009) showed that MAPK14 is the key signalling pathway involved in heat-induced testicular germ cell apoptosis, inducing Bcl2 phosphorylation, which leads to its inactivation and subsequent activation of the mitochondria-dependent death pathway, mainly as a result of an imbalance in the Bax : Bcl2 ratio. Importantly, the key components of the MAPK signalling pathway, such as extracellular signal-regulated kinase (ERK) and MAPK kinase (MEK), have also been identified within human ejaculated spermatozoa (de Lamirande and Gagnon 2002;O'Flaherty et al 2005;Almog et al 2008;Du Plessis et al 2010). …”

Section: Introductionmentioning

confidence: 99%

Bovine spermatozoa react to in vitro heat stress by activating the mitogen-activated protein kinase 14 signalling pathway

Rahman

Vandaele²,

Rijsselaere

et al. 2014

Reprod. Fertil. Dev.

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Abstract. Heat stress has long been recognised as a cause of subfertility in farm animals. The objectives of the present study were to elucidate the effect of heat stress on sperm function and involvement of the mitogen-activated protein kinase (MAPK) 14 signalling pathway. Spermatozoa incubated for 4 h at a physiological temperature (38.58C) exhibited significantly (P , 0.05) reduced motility, plasma membrane integrity and mitochondrial potential compared with nonincubated spermatozoa; the reductions in these parameters were more severe following incubation at a hyperthermic (418C) temperature (P , 0.01). Percentages of fertilisation and embryo development were highly affected in spermatozoa incubated at 418C compared with non-incubated spermatozoa (P , 0.01). Similarly, embryo quality was adversely affected by sperm incubation at 418C, as indicated by a higher apoptotic cell ratio in Day 7 blastocysts compared with that in the non-incubated control group (14.6% vs 6.7%, respectively; P , 0.01). Using SB203580 (10 mg mL À1 ), a specific inhibitor of the p38 MAPK pathway, during sperm hyperthermia reduced MAPK14 activation (24.9% vs 35.6%), increased sperm motility (45.8% vs 26.5%) and reduced DNA fragmentation (16.9% vs 23.4%) compared with the untreated control group, but did not improve subsequent fertilisation and embryo development. In conclusion, heat stress significantly affects the potential of spermatozoa to penetrate oocytes, as well as subsequent embryo development and quality. Notably, the data show that the MAPK14 signalling pathway is largely involved in heat-induced sperm damage. However, further research is needed to elucidate other signalling pathways possibly involved in heat-induced sperm damage.Additional keywords: functional parameters, mitogen-activated protein kinase 14 phosphorylation, terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling.

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Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality

Cited by 110 publications

References 56 publications

Testicular Expression of Adora3i2 in Adora3 Knockout Mice Reveals a Role of Mouse A3Ri2 and Human A3Ri3 Adenosine Receptors in Sperm*

Testicular Expression of Adora3i2 in Adora3 Knockout Mice Reveals a Role of Mouse A3Ri2 and Human A3Ri3 Adenosine Receptors in Sperm*

PKA and CaMKII mediate PI3K activation in bovine sperm by inhibition of the PKC/PP1 cascade

Bovine spermatozoa react to in vitro heat stress by activating the mitogen-activated protein kinase 14 signalling pathway

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