Sodium-Hydrogen-Exchanger expression in human sperm and its relationship with semen parameters

Zhang, Zhe; Yang, Yan; Wu, Han; Zhang, Hongliang; Mao, Jiaming; Liu, Defeng; Zhao, Lianming; Lin, Haocheng; Tang, Wenhao; Hong, Kai; Jiang, Hui

doi:10.1007/s10815-017-0898-2

Cited by 27 publications

(30 citation statements)

References 37 publications

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“…SLC9C1 (sNHE) was previously described to only localise to the principal piece of the mouse sperm flagellum 25 . Zhang et al 30 proposed the same localisation in human sperm cells, although the staining was weak and quite heterogeneous. Our immunostaining assays carried out with two different antibodies suggest a distinct flagellar profile in human sperm.…”

Section: Discussionmentioning

confidence: 96%

The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility

et al. 2021

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Asthenozoospermia, defined by the absence or reduction of sperm motility, constitutes the most frequent cause of human male infertility. This pathological condition is caused by morphological and/or functional defects of the sperm flagellum, which preclude proper sperm progression. While in the last decade many causal genes were identified for asthenozoospermia associated with severe sperm flagellar defects, the causes of purely functional asthenozoospermia are still poorly defined. We describe here the case of an infertile man, displaying asthenozoospermia without major morphological flagellar anomalies and carrying a homozygous splicing mutation in SLC9C1 (sNHE), which we identified by whole‐exome sequencing. SLC9C1 encodes a sperm‐specific sodium/proton exchanger, which in mouse regulates pH homeostasis and interacts with the soluble adenylyl cyclase (sAC), a key regulator of the signalling pathways involved in sperm motility and capacitation. We demonstrate by means of RT‐PCR, immunodetection and immunofluorescence assays on patient's semen samples that the homozygous splicing mutation (c.2748 + 2 T > C) leads to in‐frame exon skipping resulting in a deletion in the cyclic nucleotide‐binding domain of the protein. Our work shows that in human, similar to mouse, SLC9C1 is required for sperm motility. Overall, we establish a homozygous truncating mutation in SLC9C1 as a novel cause of human asthenozoospermia and infertility.

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Section: Discussionmentioning

confidence: 96%

The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility

et al. 2021

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“…The SLC9 gene family encodes 13 evolutionarily conserved NHE. The expression of three NHEs has been identified in rat, mouse and human sperm, such as NHE1, NHE5, and NHE10 (Woo et al, 2002 ; Wang et al, 2003a ; Zhang et al, 2017 ). Furthermore, in mouse sperm, a new member of the NHE family (sperm-specific NHE; sNHE, Slc9c1 gene) is expressed, whose localization is restricted to the principal piece (Wang et al, 2003a ).…”

Section: Extracellular and Intracellular Ph In Human Spermmentioning

confidence: 99%

“…In human sperm, sNHE is mainly localized in the principal piece and its expression is downregulated in sperm from asthenozoospermic patients (Zhang et al, 2017 ). In addition, it has been reported that regulation of pHi in human sperm depends on the [Na + ] e , and that ethyl-isopropyl amiloride (EIPA) affects this regulation within concentrations that inhibit NHE activity (Garcia and Meizel, 1999 ).…”

Section: Extracellular and Intracellular Ph In Human Spermmentioning

confidence: 99%

Molecular Basis of Human Sperm Capacitation

Molina

Luque

Balestrini

et al. 2018

Front. Cell Dev. Biol.

161

186

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In the early 1950s, Austin and Chang independently described the changes that are required for the sperm to fertilize oocytes in vivo. These changes were originally grouped under name of “capacitation” and were the first step in the development of in vitro fertilization (IVF) in humans. Following these initial and fundamental findings, a remarkable number of observations led to characterization of the molecular steps behind this process. The discovery of certain sperm-specific molecules and the possibility to record ion currents through patch-clamp approaches helped to integrate the initial biochemical observation with the activity of ion channels. This is of particular importance in the male gamete due to the fact that sperm are transcriptionally inactive. Therefore, sperm must control all these changes that occur during their transit through the male and female reproductive tracts by complex signaling cascades that include post-translational modifications. This review is focused on the principal molecular mechanisms that govern human sperm capacitation with particular emphasis on comparing all the reported pieces of evidence with the mouse model.

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“…Four isoforms (isoenzymes) of NHE have been identified so far on the sperm cell plasma membrane, namely NHE1, NHE5, mtsNHE (testis-specific NHE) and NHE10. The latter is also known as the sperm-specific NHE isoform (sNHE) as it is exclusively expressed in spermatozoa (Martins et al 2014, Zhang et al 2017 and has been already shown, similarly to mtsNHE, to play a role in affecting sperm motility (Wang et al 2003, Liu et al 2010, Zhang et al 2017. Decreased motility, responsible for selective male infertility, and associated to sperm morpho-functional abnormalities, was also described in mice null for the organellar NHE8 isoform (Oberheide et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

et al. 2018

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Sperm motility, a feature essential for fertilization, is influenced by intracellular pH (pH) homeostasis. Several mechanisms are involved in pH regulation, among which sodium-hydrogen exchangers (NHEs), a family of integral transmembrane proteins that catalyze the exchange of Na for H across lipid bilayers. A preliminary characterization of NHE activity and kinetic parameters, followed by analysis of the expression and localization of the protein in ram spermatozoa was performed. NHE activity showed an apparent for external Na of 17.61 mM. Immunoblotting revealed a molecular mass of 85 kDa. Immunolocalization pattern showed some species-specific aspects, such as positive labeling at the equatorial region of the sperm head. Cariporide, a selective NHE1 inhibitor, significantly reduced pH recovery (85%). Similarly, exposure to cariporide significantly inhibited different motility parameters, including those related to sperm capacitation. fertilization (IVF) was not affected by cariporide, possibly due to the non-dramatic, although significant, drop in motility and velocity parameters or due to prolonged exposure during IVF, which may have caused progressive loss of its inhibitory effect. In conclusion, this is the first study documenting, in a large animal model (sheep) of well-known translational relevance, a direct functional role of NHE on sperm pH and motility. The postulated specificity of cariporide toward isoform 1 of the Na/H exchanger seems to suggest that NHE1 may contribute to the observed effects on sperm cell functionality.

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Sodium-Hydrogen-Exchanger expression in human sperm and its relationship with semen parameters

Abstract: The expression pattern of sNHE suggested that this protein may be involved in the regulation of sperm motility, and aberration of its expression in sperm may contribute to the pathogenesis of asthenozoospermia.

Cited by 27 publications

References 37 publications

The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility

The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility

Molecular Basis of Human Sperm Capacitation

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

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