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Recent Advances in the Physiology of Ion Channels in Sperm Cells

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 11336

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Special Issue Editor

Prof. Dr. Elisabeth Pinart

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Guest Editor

Unit of Cell Biology, Biotechnology of Animal and Human Reproduction (TechnoSperm), Department of Biology, Faculty of Sciences, Institute of Food and Agricultural Technology, University of Girona, E-17003 Girona, Spain
Interests: sperm physiology; flow cytometry; sperm motility; boar reproduction; sperm maturation; sperm capacitation; ion channels; immunocytochemistry; sperm cryopreservation
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Special Issue Information

Dear Colleagues,

Ion transport is essential for sperm physiology, being involved in sperm-cell differentiation and maturation, motility activation, chemotaxis towards the oocyte, and fertilization, as well as in sperm adaptation to the surrounding medium. In mammals, the flux of calcium (Ca²⁺) and bicarbonate (HCO₃⁻) across the sperm plasma membrane has been extensively reported, due to the relevance of both ions as second messengers triggering sperm capacitation in the female tract. However, other ions such as potassium (K⁺), sodium (Na⁺), chloride (Cl⁻), and hydrogen (H⁺) are also relevant to male fertility, not only during sperm capacitation but also throughout spermiogenesis and epididymal maturation and upon ejaculation. The plasma membrane of mature sperm contains a high diversity of ion transporters belonging to different protein families and showing different ion affinity, regulation mechanisms, and functional multiplicity. Interestingly, some types of ion channels are present in most species but differing in their content and regulation mechanisms, thus highlighting that sperm physiology is species-specific.

Recent evidence also highlights the relevance of ion transport in male fertility in nonmammal species, despite further research being necessary to better understand the sperm physiology in these species.

This Special Issue of IJMS is the continuation of two previous Special Issues, “Ion Channels of Spermatozoa: Structure, Function, and Regulation Mechanisms” and “Sperm Physiology 2.0”. The quality and novelty of the publications included in both Special Issues highlight the importance of ion channels in male fertility. In this regard, the absence or dysfunction of even a single channel type may result in male subfertility or affect sperm cryotolerance; moreover, some ion channels can be used as contraception targets. The purpose of this new Special Issue is to compile the latest advances in the knowledge, and so it welcomes novel research or insightful reviews on the role of ion channels in sperm function and physiology in mammal and nonmammal species. Submissions dealing with the effects of pathologies or sperm processing in ion channel function, as well as comparisons of ion channel content and function between species, are also welcomed.

I look forward to receiving your contributions.

Prof. Dr. Elisabeth Pinart
Guest Editor

Manuscript Submission Information

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Keywords

sperm physiology
spermatogenesis
sperm maturation
sperm capacitation
plasma membrane potential
ionic conductance
cryopreservation
sperm sample processing
fertilization

Published Papers (7 papers)

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Research

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14 pages, 2045 KiB

Open AccessArticle

Membrane Cholesterol Inhibits Progesterone-Mediated Sperm Function through the Possible Involvement of ABHD2

by Luca De Toni, Ilaria Cosci, Iva Sabovic, Andrea Di Nisio, Diego Guidolin, Federica Pedrucci, Federica Finocchi, Stefano Dall’Acqua, Carlo Foresta, Alberto Ferlin and Andrea Garolla

Int. J. Mol. Sci. 2023, 24(11), 9254; https://doi.org/10.3390/ijms24119254 - 25 May 2023

Cited by 1 | Viewed by 1206

Abstract

Abhydrolase domain containing 2-acylglycerol lipase (ABHD2) was recently claimed as the membrane receptor of progesterone (P4) in sperm cells, mediating cell processes such as sperm chemotaxis and acrosome reaction. Here, we investigated the role of membrane cholesterol (Chol) on ABHD2-mediated human sperm chemotaxis. Human sperm cells were obtained from twelve normozoospemic healthy donors. ABHD2–Chol interaction was modelled by computational molecular-modelling (MM). Sperm membrane Chol content was depleted by incubating cells with cyclodextrin (CD) or augmented by the incubation with the complex between CD and Chol (CD:Chol). Cell Chol levels were quantified by liquid chromatography-mass spectrometry. Sperm migration upon P4 gradient was evaluated through the accumulation assay in a specific migration device. Motility parameters were evaluated by sperm class analyzer, whilst intracellular calcium concentration, acrosome reaction and mitochondrial membrane potential were evaluated with calcium orange, FITC-conjugated anti-CD46 antibody and JC-1 fluorescent probes, respectively. MM analysis showed the possible stable binding Chol to ABHD2, resulting in to major impact on the protein backbone flexibility. The treatment with CD was associated with a dose-dependent increase in sperm migration in a 160 nM P4 gradient, together with increase in sperm motility parameters and levels of acrosome reaction. The treatment with CD:Chol was associated with essentially opposite effects. Chol was, thus, suggested to inhibit P4-mediated sperm function through the possible inhibition of ABHD2. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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14 pages, 2594 KiB

Open AccessArticle

Hamster Sperm Possess Functional Na⁺/Ca²⁺-Exchanger 1: Its Implication in Hyperactivation

by Gen L. Takei, Yuhei Ogura, Yoshihiro Ujihara, Fubito Toyama, Keitaro Hayashi and Tomoe Fujita

Int. J. Mol. Sci. 2023, 24(10), 8905; https://doi.org/10.3390/ijms24108905 - 17 May 2023

Cited by 1 | Viewed by 1472

Abstract

Previous studies demonstrated that hamster sperm hyperactivation is suppressed by extracellular Na⁺ by lowering intracellular Ca²⁺ levels, and Na⁺/Ca²⁺-exchanger (NCX) specific inhibitors canceled the suppressive effects of extracellular Na⁺. These results suggest the involvement of NCX in the regulation of hyperactivation. However, direct evidence of the presence and functionality of NCX in hamster spermatozoa is still lacking. This study aimed to reveal that NCX is present and is functional in hamster spermatozoa. First, NCX1 and NCX2 transcripts were detected via RNA-seq analyses of hamster testis mRNAs, but only the NCX1 protein was detected. Next, NCX activity was determined by measuring the Na⁺-dependent Ca²⁺ influx using the Ca²⁺ indicator Fura-2. The Na⁺-dependent Ca²⁺ influx was detected in hamster spermatozoa, notably in the tail region. The Na⁺-dependent Ca²⁺ influx was inhibited by the NCX inhibitor SEA0400 at NCX1-specific concentrations. NCX1 activity was reduced after 3 h of incubation in capacitating conditions. These results, together with authors’ previous study, showed that hamster spermatozoa possesses functional NCX1 and that its activity was downregulated upon capacitation to trigger hyperactivation. This is the first study to successfully reveal the presence of NCX1 and its physiological function as a hyperactivation brake. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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19 pages, 2901 KiB

Open AccessArticle

Pharmacological Evidence Suggests That Slo3 Channel Is the Principal K⁺ Channel in Boar Spermatozoa

by Akila Cooray, Jeongsook Kim, Beno Ramesh Nirujan, Nishani Jayanika Jayathilake and Kyu Pil Lee

Int. J. Mol. Sci. 2023, 24(9), 7806; https://doi.org/10.3390/ijms24097806 - 25 Apr 2023

Viewed by 1439

Abstract

Sperm ion channels are associated with the quality and type of flagellar movement, and their differential regulation is crucial for sperm function during specific phases. The principal potassium ion channel is responsible for the majority of K⁺ ion flux, resulting in membrane hyperpolarization, and is essential for sperm capacitation-related signaling pathways. The molecular identity of the principal K⁺ channel varies greatly between different species, and there is a lack of information about boar K⁺ channels. We aimed to determine the channel identity of boar sperm contributing to the primary K⁺ current using pharmacological dissection. A series of Slo1 and Slo3 channel modulators were used for treatment. Sperm motility and related kinematic parameters were monitored using a computer-assisted sperm analysis system under non-capacitated conditions. Time-lapse flow cytometry with fluorochromes was used to measure changes in different intracellular ionic concentrations, and conventional flow cytometry was used to determine the acrosome reaction. Membrane depolarization, reduction in acrosome reaction, and motility parameters were observed upon the inhibition of the Slo3 channel, suggesting that the Slo3 gene encodes the main K⁺ channel in boar spermatozoa. The Slo3 channel was localized on the sperm flagellum, and the inhibition of Slo3 did not reduce sperm viability. These results may aid potential animal-model-based extrapolations and help to ameliorate motility and related parameters, leading to improved assisted reproductive methods in industrial livestock production. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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18 pages, 41376 KiB

Open AccessArticle

Alkaline Dilution Alters Sperm Motility in Dairy Goat by Affecting sAC/cAMP/PKA Pathway Activity

by Qifu He, Feng Gao, Shenghui Wu, Shaowen Wang, Zhiming Xu, Xuerui Xu, Tianyang Lan, Kang Zhang and Fusheng Quan

Int. J. Mol. Sci. 2023, 24(2), 1771; https://doi.org/10.3390/ijms24021771 - 16 Jan 2023

Cited by 1 | Viewed by 2233

Abstract

In dairy goat farming, increasing the female kid rate is beneficial to milk production and is, therefore, economically beneficial to farms. Our previous study demonstrated that alkaline incubation enriched the concentration of X-chromosome-bearing sperm; however, the mechanism by which pH affects the motility of X-chromosome-bearing sperm remains unclear. In this study, we explored this mechanism by incubating dairy goat sperm in alkaline dilutions, examining the pattern of changes in sperm internal pH and Ca²⁺ concentrations and investigating the role of the sAC/cAMP/PKA pathway in influencing sperm motility. The results showed that adding a calcium channel inhibitor during incubation resulted in a concentration-dependent decrease in the proportion of spermatozoa with forward motility, and the sperm sAC protein activity was positively correlated with the calcium ion concentration (r = 0.9972). The total motility activity, proportion of forward motility, and proportion of X-chromosome-bearing sperm decreased (p < 0.05) when cAMP/PKA protease activity was inhibited. Meanwhile, the enrichment of X-chromosome-bearing sperm by pH did not affect the sperm capacitation state. These results indicate that alkaline dilution incubation reduces Ca²⁺ entry into X-sperm and the motility was slowed down through the sAC/cAMP/PKA signaling pathway, providing a theoretical foundation for further optimization of the sex control method. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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Review

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32 pages, 3949 KiB

Open AccessReview

Na⁺/H⁺ Exchangers (NHEs) in Mammalian Sperm: Essential Contributors to Male Fertility

by Cameron C. Gardner and Paul F. James

Int. J. Mol. Sci. 2023, 24(19), 14981; https://doi.org/10.3390/ijms241914981 - 07 Oct 2023

Cited by 1 | Viewed by 1092

Abstract

Na⁺/H⁺ exchangers (NHEs) are known to be important regulators of pH in multiple intracellular compartments of eukaryotic cells. Sperm function is especially dependent on changes in pH and thus it has been postulated that NHEs play important roles in regulating the intracellular pH of these cells. For example, in order to achieve fertilization, mature sperm must maintain a basal pH in the male reproductive tract and then alkalize in response to specific signals in the female reproductive tract during the capacitation process. Eight NHE isoforms are expressed in mammalian testis/sperm: NHE1, NHE3, NHE5, NHE8, NHA1, NHA2, NHE10, and NHE11. These NHE isoforms are expressed at varying times during spermatogenesis and localize to different subcellular structures in developing and mature sperm where they contribute to multiple aspects of sperm physiology and male fertility including proper sperm development/morphogenesis, motility, capacitation, and the acrosome reaction. Previous work has provided evidence for NHE3, NHE8, NHA1, NHA2, and NHE10 being critical for male fertility in mice and NHE10 has recently been shown to be essential for male fertility in humans. In this article we review what is known about each NHE isoform expressed in mammalian sperm and discuss the physiological significance of each NHE isoform with respect to male fertility. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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16 pages, 1336 KiB

Open AccessReview

The Cation/Calcium Channel of Sperm (CatSper): A Common Role Played Despite Inter-Species Variation?

by Alejandro Vicente-Carrillo, Manuel Álvarez-Rodríguez and Heriberto Rodriguez-Martinez

Int. J. Mol. Sci. 2023, 24(18), 13750; https://doi.org/10.3390/ijms241813750 - 06 Sep 2023

Cited by 1 | Viewed by 864

Abstract

The main cation/calcium channel of spermatozoa (CatSper), first identified in 2001, has been thoroughly studied to elucidate its composition and function, while its distribution among species and sperm sources is yet incomplete. CatSper is composed of several subunits that build a pore-forming calcium channel, mainly activated in vivo in ejaculated sperm cells by intracellular alkalinization and progesterone, as suggested by the in vitro examinations. The CatSper channel relevance is dual: to maintain sperm homeostasis (alongside the plethora of membrane channels present) as well as being involved in pre-fertilization events, such as sperm capacitation, hyperactivation of sperm motility and the acrosome reaction, with remarkable species differences. Interestingly, the observed variations in CatSper localization in the plasma membrane seem to depend on the source of the sperm cells explored (i.e., epididymal or ejaculated, immature or mature, processed or not), the method used for examination and, particularly, on the specificity of the antibodies employed. In addition, despite multiple findings showing the relevance of CatSper in fertilization, few studies have studied CatSper as a biomarker to fine-tune diagnosis of sub-fertility in livestock or even consider its potential to control fertilization in plague animals, a more ethically defensible strategy than implicating CatSper to pharmacologically modify male-related fertility control in humans, pets or wild animals. This review describes inter- and intra-species differences in the localization, structure and function of the CatSper channel, calling for caution when considering its potential manipulation for fertility control or improvement. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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15 pages, 2198 KiB

Open AccessReview

SLO3: A Conserved Regulator of Sperm Membrane Potential

by Maximilian D. Lyon, Juan J. Ferreira, Ping Li, Shweta Bhagwat, Alice Butler, Kelsey Anderson, Maria Polo and Celia M. Santi

Int. J. Mol. Sci. 2023, 24(13), 11205; https://doi.org/10.3390/ijms241311205 - 07 Jul 2023

Cited by 1 | Viewed by 2220

Abstract

Sperm cells must undergo a complex maturation process after ejaculation to be able to fertilize an egg. One component of this maturation is hyperpolarization of the membrane potential to a more negative value. The ion channel responsible for this hyperpolarization, SLO3, was first cloned in 1998, and since then much progress has been made to determine how the channel is regulated and how its function intertwines with various signaling pathways involved in sperm maturation. Although Slo3 was originally thought to be present only in the sperm of mammals, recent evidence suggests that a primordial form of the gene is more widely expressed in some fish species. Slo3, like many reproductive genes, is rapidly evolving with low conservation between closely related species and different regulatory and pharmacological profiles. Despite these differences, SLO3 appears to have a conserved role in regulating sperm membrane potential and driving large changes in response to stimuli. The effect of this hyperpolarization of the membrane potential may vary among mammalian species just as the regulation of the channel does. Recent discoveries have elucidated the role of SLO3 in these processes in human sperm and provided tools to target the channel to affect human fertility. Full article

(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)

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