Signaling mechanisms in mammalian sperm motility&lt;sup&gt;&lt;xref ref-type="fn" rid="afn1"&gt;†&lt;/xref&gt;&lt;/sup&gt;

Freitas, Maria João; Vijayaraghavan, Srinivasan; Fardilha, Margarida

doi:10.1095/biolreprod.116.144337

Cited by 54 publications

(28 citation statements)

References 124 publications

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“…To acquire progressive motility and fertility competence, sperm need to undergo two post-testicular maturation processes, i.e. the one occurring in the male epididymis is known as epididymal sperm maturation and the other is designated as capacitation expressed in the female reproductive tract ( Freitas et al, 2017 ). On the other hand, both of these changes are associated with sequential biochemical changes occurring in different sperm segments ( Freitas et al, 2017 ; Gervasi and Visconti, 2017 ; Puga Molina et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression

Liu

Zhang

Wang

et al. 2020

Journal of Molecular Cell Biology

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After leaving the testis, mammalian sperm undergo a sequential maturation process in the epididymis followed by capacitation during their movement through the female reproductive tract. These phenotypic changes are associated with modification of protein phosphorylation and membrane remodeling, which is requisite for sperm to acquire forward motility and induce fertilization. However, the molecular mechanisms underlying sperm maturation and capacitation are still not fully understood. Herein, we show that PPP3R2, a testis-specific regulatory subunit of protein phosphatase 3 (an isoform of calcineurin in the testis), is essential for sperm maturation and capacitation. Knockout of Ppp3r2 in mice leads to male sterility due to sperm motility impairment and morphological defects. One very noteworthy change includes increases in sperm membrane stiffness. Moreover, PPP3R2 regulates sperm maturation and capacitation via (i) modulation of membrane diffusion barrier function at the annulus and (ii) facilitation of cholesterol efflux during sperm capacitation. Taken together, PPP3R2 plays a critical role in modulating cholesterol efflux and mediating the dynamic control of membrane remodeling during sperm maturation and capacitation.

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Section: Introductionmentioning

confidence: 99%

Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression

Liu

Zhang

Wang

et al. 2020

Journal of Molecular Cell Biology

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“…These signaling enzymes, protein phosphatase 1 (PP1), glycogen synthase kinase 3 (GSK3) and the calcium activated phosphatase (PP2B), affect sperm function in the epididymis and in the female reproductive tract. Several reviews detail the roles of sperm cAMP-PKA and calcium metabolism (Visconti et al, 2002;Burton and McKnight, 2007;Buffone et al, 2014;Stival et al, 2016;Freitas et al, 2017;Balbach et al, 2018;Leemans et al, 2019;Stewart and Davis, 2019). Following a brief summary of the actions of cAMP-PKA, calcium and pH, the remainder of the review will be focused largely devoted to examination of the key roles of PP1, GSK3, and calcium activated protein phosphatase, PP2B (PPP3R2/CC) in mediating the actions of the second messengers during sperm maturation and fertilization.…”

Section: Introductionmentioning

confidence: 99%

Signaling Enzymes Required for Sperm Maturation and Fertilization in Mammals

Dey

Brothag

Vijayaraghavan

2019

Front. Cell Dev. Biol.

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In mammals, motility and fertilizing ability of spermatozoa develop during their passage through the epididymis. After ejaculation, sperm undergo capacitation and hyperactivation in the female reproductive tract-a motility transition that is required for sperm penetration of the egg. Both epididymal initiation of sperm motility and hyperactivation are essential for male fertility. Motility initiation in the epididymis and sperm hyperactivation involve changes in metabolism, cAMP (cyclic adenosine monophosphate), calcium and pH acting through protein kinases and phosphatases. Despite this knowledge, we still do not understand, in biochemical terms, how sperm acquire motility in the epididymis and how motility is altered in the female reproductive tract. Recent data show that the sperm specific protein phosphatase PP1γ2, glycogen synthase kinase 3 (GSK3), and the calcium regulated phosphatase calcineurin (PP2B), are involved in epididymal sperm maturation. The protein phosphatase PP1γ2 is present only in testis and sperm in mammals. PP1γ2 has a isoform-specific requirement for normal function of mammalian sperm. Sperm PP1γ2 is regulated by three proteinsinhibitor 2, inhibitor 3 and SDS22. Changes in phosphorylation of these three inhibitors and their binding to PP1γ2 are involved in initiation and activation of sperm motility. The inhibitors are phosphorylated by protein kinases, one of which is GSK3. The isoform GSK3α is essential for epididymal sperm maturation and fertility. Calcium levels dramatically decrease during sperm maturation and initiation of motility suggesting that the calcium activated sperm phosphatase (PP2B) activity also decreases. Loss of PP2B results in male infertility due to impaired sperm maturation in the epididymis. Thus the three signaling enzymes PP1γ2, GSK3, and PP2B along with the documented PKA (protein kinase A) have key roles in sperm maturation and hyperactivation. Significantly, all these four signaling enzymes are present as specific isoforms only in placental mammals, a testimony to their essential roles in the unique aspects of sperm function in mammals. These findings should lead to a better biochemical understanding of the basis of male infertility and should lead to novel approaches to a male contraception and managed reproduction.

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“…Although there were no significant differences in the phosphorylation levels at the phosphotyrosine site (Y623) of FSIP2, this site was identified as a new phosphosite ( Supplementary Data 3 ); a previous study reported different sites (Y630, Y1635, Y6101, and Y6351) [ 16 ]. In the sperm principal piece, the fibrous sheath supports signaling proteins that regulate motility, capacitation, and hyperactivation [ 29 ]. The major components of the sheath are AKAP3 and AKAP4, which probably form the integral cytoskeleton structure [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomics and Bioinformatics Analyses Reveal Key Roles of GSK-3 and AKAP4 in Mouse Sperm Capacitation

Syifa

Yang

et al. 2020

IJMS

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Protein phosphorylation can induce signal transduction to change sperm motility patterns during sperm capacitation. However, changes in the phosphorylation of sperm proteins in mice are still incompletely understood. Here, capacitation-related phosphorylation in mouse sperms were firstly investigated by label-free quantitative (LFQ) phosphoproteomics coupled with bioinformatics analysis using ingenuity pathway analysis (IPA) methods such as canonical pathway, upstream regulator, and network analysis. Among 1632 phosphopeptides identified at serine, threonine, and tyrosine residues, 1050 novel phosphosites, corresponding to 402 proteins, were reported. Gene heatmaps for IPA canonical pathways showed a novel role for GSK-3 in GP6 signaling pathways associated with capacitation for 60 min. At the same time, the reduction of the abundant isoform-specific GSK-3α expression was shown by western blot (WB) while the LFQ pY of this isoform slightly decreased and then increased. The combined results from WB and LFQ methods explain the less inhibitory phosphorylation of GSK-3α during capacitation and also support the predicted increases in its activity. In addition, pAKAP4 increased at the Y156 site but decreased at the Y811 site in a capacitated state, even though IPA network analysis and WB analysis for overall pAKAP revealed upregulated trends. The potential roles of GSK-3 and AKAP4 in fertility are discussed.

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Signaling mechanisms in mammalian sperm motility<sup><xref ref-type="fn" rid="afn1">†</xref></sup>

Cited by 54 publications

References 124 publications

Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression

Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression

Signaling Enzymes Required for Sperm Maturation and Fertilization in Mammals

Phosphoproteomics and Bioinformatics Analyses Reveal Key Roles of GSK-3 and AKAP4 in Mouse Sperm Capacitation

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