The Ca2+-activated K+ current of human sperm is mediated by Slo3

Brenker, Christoph; Zhou, Yu; Müller, Astrid M.; Pereda, Alberto E.; Trötschel, Christian; Poetsch, Ansgar; Xia, Xiaoming; Bönigk, Wolfgang; Lingle, Christopher J.; Kaupp, U. Benjamin; Strünker, Timo

doi:10.7554/elife.01438

Cited by 92 publications

(168 citation statements)

References 60 publications

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“…From these biophysical properties as well as the pharmacological profile, human KSper seems to resemble the calcium-activated big conductance potassium channel Slo1 (KCNMA1) [20]. Recently other models were proposed suggesting that human capacitated spermatozoa possess a different type of Slo channel [145] or even a modified version of Slo3 that is calcium-sensitive and weakly pH-dependent [144], an unusual set of properties for this type of ion channel (Fig. 2).…”

Section: Potassium Channels Of Spermmentioning

confidence: 95%

“…While Slo3 was also expected to form the potassium channel of human sperm, recent recording from ejaculated human spermatozoa indicates that in clear contrast to murine sperm, human sperm potassium current (KSper) is pH-independent and sensitive to [Ca 2+ ] i [20]. Furthermore, it could also be inhibited by progesterone [20,144]. From these biophysical properties as well as the pharmacological profile, human KSper seems to resemble the calcium-activated big conductance potassium channel Slo1 (KCNMA1) [20].…”

Section: Potassium Channels Of Spermmentioning

confidence: 99%

“…Furthermore, the crystal structure of human Slo3 indicated the channel lacks a calcium-sensitive bowl [142]. One apparent difference is that both studies used slightly different human sperm cells: capacitated [144] versus noncapacitated cells [20], but another possible explanation could be that KSper consists of a heteromer of Slo1 and Slo3 subunits [145,149]. While Slo channels exist as tetrameric complexes of alpha subunits (Slo1 or Slo3) and auxiliary gamma subunits (LRCC26 or LRCC52), additional beta subunits can change their biophysical and pharmacological properties [140,150,151].…”

Section: Potassium Channels Of Spermmentioning

confidence: 99%

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Flagellar ion channels of sperm: similarities and differences between species

et al. 2015

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a b s t r a c tMotility and fertilization potential of mammalian sperm are regulated by ion homeostasis which in turn is under tight control of ion channels and transporters. Sperm intracellular pH, membrane voltage and calcium concentration ([Ca 2+ ] i ) are all important for sperm activity within the female reproductive tract. While all mammalian sperm are united in their goal to find and fertilize an egg, the molecular mechanisms they utilize for this purpose are diverse and differ between species especially on the level of ion channels. Recent direct recording from sperm cells of different species indicate the differences between rodent, non-human primate, ruminant, and human sperm on the basic levels of their ion channel regulation. In this review we summarize the current knowledge about ion channel diversity of the animal kingdom and concentrate our attention on flagellar ion channels of mammalian sperm.

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Section: Potassium Channels Of Spermmentioning

confidence: 95%

Section: Potassium Channels Of Spermmentioning

confidence: 99%

Section: Potassium Channels Of Spermmentioning

confidence: 99%

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Flagellar ion channels of sperm: similarities and differences between species

et al. 2015

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“…In mouse sperm, alkalization leads to activation of two spermspecific channels, the Ca 2+ -permeable CATSPER channel (8-10, 13) and the K + -permeable KSPER K + channel (14, 15). KSPER and CATSPER currents are also present in human sperm (16-18), although intriguingly there seem to be differences in regulation of each channel type between mice and humans (11,12,17).Despite the species-specific differences in the details of their regulation, KSPER and CATSPER are of central importance in sperm function and fertility in both humans and mice. In mouse sperm, KSPER and CATSPER together account for all patchclamp measurable cation current activated by voltage and alkalization (19) and are thought to act in concert to mediate the changes in membrane cation conductance and Ca 2+ influx that occur during the onset of capacitation (14,20).…”

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confidence: 99%

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SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility

Zeng

Yang

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Following entry into the female reproductive tract, mammalian sperm undergo a maturation process termed capacitation that results in competence to fertilize ova. Associated with capacitation is an increase in membrane conductance to both Ca 2+ and K + , leading to an elevation in cytosolic Ca 2+ critical for activation of hyperactivated swimming motility. In mice, the Ca 2+ conductance (alkalization-activated Ca 2+ -permeable sperm channel, CATSPER) arises from an ensemble of CATSPER subunits, whereas the K + conductance (sperm pH-regulated K + current, KSPER) arises from a poreforming ion channel subunit encoded by the slo3 gene (SLO3) subunit. In the mouse, both CATSPER and KSPER are activated by cytosolic alkalization and a concerted activation of CATSPER and KSPER is likely a common facet of capacitation-associated increases in Ca 2+ and K + conductance among various mammalian species. The properties of heterologously expressed mouse SLO3 channels differ from native mouse KSPER current. Recently, a potential KSPER auxiliary subunit, leucine-rich-repeat-containing protein 52 (LRRC52), was identified in mouse sperm and shown to shift gating of SLO3 to be more equivalent to native KSPER. Here, we show that genetic KO of LRRC52 results in mice with severely impaired fertility. Activation of KSPER current in sperm lacking LRRC52 requires more positive voltages and higher pH than for WT KSPER. These results establish a critical role of LRRC52 in KSPER channels and demonstrate that loss of a non-pore-forming auxiliary subunit results in severe fertility impairment. Furthermore, through analysis of several genotypes that influence KSPER current properties we show that in vitro fertilization competence correlates with the net KSPER conductance available for activation under physiological conditions. sperm fertility | KSPER | SLO3 channels | auxiliary subunits U pon entry into the female reproductive tract, mammalian sperm undergo a sequence of maturational steps, collectively termed capacitation, to become competent to fertilize an egg (1, 2). Two important components of this process, thought to be shared among mammalian species, are cytosolic alkalization (3-5) and then an associated increase in cytosolic Ca 2+ (6, 7). These events are coupled with changes in ionic fluxes in sperm membrane. Over the past 10 y, the application of patch-clamp recording to individual sperm (8) has allowed identification of ionic currents that respond to alkalization and/or Ca 2+ (9-12). In mouse sperm, alkalization leads to activation of two spermspecific channels, the Ca 2+ -permeable CATSPER channel (8-10, 13) and the K + -permeable KSPER K + channel (14, 15). KSPER and CATSPER currents are also present in human sperm (16-18), although intriguingly there seem to be differences in regulation of each channel type between mice and humans (11,12,17).Despite the species-specific differences in the details of their regulation, KSPER and CATSPER are of central importance in sperm function and fertility in both humans and mice. In mouse spe...

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Premammalian origin of the sperm‐specific Slo3 channel

Vicens¹,

Andrade-López²,

Cortez

et al. 2017

FEBS Open Bio

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Slo3 is a sperm‐specific potassium (K+) channel essential for male fertility. Slo3 channels have so far been considered to be specific to mammals. Through exploratory genomics, we identified the Slo3 gene in the genome of terrestrial (birds and reptiles) and aquatic (fish) vertebrates. In the case of fish, Slo3 has undergone several episodes of gene loss. Transcriptomic analysis showed that vertebrate Slo3 transcript orthologues are predominantly expressed in testis, in concordance with the mammalian Slo3. We conclude that the Slo3 gene arose during the radiation of early vertebrates, much earlier than previously thought. Our findings add to the growing evidence indicating that the phylogenetic profiles of sperm‐specific channels are intermittent throughout metazoan evolution, which probably reflects the adaptation of sperm to different ionic milieus and fertilization environments.

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The Ca2+-activated K+ current of human sperm is mediated by Slo3

Cited by 92 publications

References 60 publications

Flagellar ion channels of sperm: similarities and differences between species

Flagellar ion channels of sperm: similarities and differences between species

SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility

Premammalian origin of the sperm‐specific Slo3 channel

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