Genetic male infertility and mutation of CATSPER ion channels

Hildebrand, Michael S.; Avenarius, Matthew R.; Fellous, Marc; Zhang, Yuzhou; Meyer, Nicole C.; Auer, J.; Serres, Catherine; Kahrizi, Kimia; Najmabadi, Hossein; Beckmann, Jacques S.; Smith, Richard J.H.

doi:10.1038/ejhg.2010.108

Cited by 117 publications

(96 citation statements)

References 43 publications

(92 reference statements)

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“…Loss of any one member of the complex is detrimental to male fertility due to their interdependent protein expression in spermatozoa though CatSper␤ and CatSper␥ null mice have yet to be observed [9,19,22,24,49,74]. Humans with mutations within the CatSper1 or CatSper2 genes were also shown to be infertile revealing CatSper's importance as a general mechanism in mammalian fertility potential [6,[75][76][77][78][79][80]. By combining mouse genetics with sperm patch clamp method CatSper activity was eventually directly recorded in 2006 and CatSper was established as the principal Ca 2+ channel of mouse sperm [16].…”

Section: Calcium Channels and Hyperactivationmentioning

confidence: 99%

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: Calcium Channels and Hyperactivationmentioning

confidence: 99%

Flagellar ion channels of sperm: similarities and differences between species

et al. 2015

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“…I CatSper is a complex ion channel encoded by four separate gene products that comprise the pore lining subunits (CatSper1-4) and at least three accessory membrane-spanning subunits: β, γ (13), and δ (14). The CatSper channel is activated by increasing alkalinity and is absolutely required for fertility in mammals, such as mice and humans (4,(14)(15)(16)(17)(18)(19). I KSper (12) is encoded by mSlo3, a sperm-specific K + channel with reduced K + selectivity and sensitivity to pH (20,21).…”

Section: −/−mentioning

confidence: 99%

ATP-activated P2X2 current in mouse spermatozoa

Navarro

Miki

Clapham

2011

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

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Sperm cells acquire hyperactivated motility as they ascend the female reproductive tract, which enables them to overcome barriers and penetrate the cumulus and zona pellucida surrounding the egg. This enhanced motility requires Ca 2+ entry via cation channel of sperm (CatSper) Ca 2+ -selective ion channels in the sperm tail. Ca 2+ entry via CatSper is enhanced by the membrane hyperpolarization mediated by Slo3, a K + channel also present in the sperm tail. To date, no transmitter-mediated currents have been reported in sperm and no currents have been detected in the head or midpiece of mature spermatozoa. We screened a number of neurotransmitters and biomolecules to examine their ability to induce ion channel currents in the whole spermatozoa. Surprisingly, we find that none of the previously reported neurotransmitter receptors detected by antibodies alone are functional in mouse spermatozoa. Instead, we find that mouse spermatozoa have a cation-nonselective current in the midpiece of spermatozoa that is activated by external ATP, consistent with an ATP-mediated increase in intracellular Ca 2+ as previously reported. The ATP-dependent current is not detected in mice lacking the P2X2 receptor gene (P2rx2). Furthermore, the slowly desensitizing and strongly outwardly rectifying ATP-gated current has the biophysical and pharmacological properties that mimic heterologously expressed mouse P2X2. We conclude that the ATP-induced current on mouse spermatozoa is mediated by the P2X2 purinergic receptor/channel. Despite the loss of ATP-gated current, P2rx2 −/− spermatozoa have normal progressive motility, hyperactivated motility, and acrosome reactions. However, fertility of P2rx2 −/− males declines with frequent mating over days, suggesting that P2X2 receptor adds a selection advantage under these conditions. infertility | P2X channel | purinergic ion channel | reproduction

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“…The absence of CatSper channels was shown to cause male infertility in mice (6,10,14), primarily because of an inability of sperm to hyperactivate (4,5). Reported cases of male infertility in patients, linked to the mutation or deletion in CatSper genes, were assumed to share the same etiology; however, no physiological data have been provided (3,8,12,13,16). Recently, we and others reported that the female steroid hormone progesterone, an important physiological activator of spermatozoa within the female reproductive tract, activates the principal Ca 2+ channel of human sperm (17,18), presumably CatSper.…”

mentioning

confidence: 99%

“…Mutation or absence of some ion channels directly affects male fertility of mice and humans (1)(2)(3)(4)(5)(6). Sperm Ca 2+ signaling is especially important for male fertility (7), and defects in the primary calcium channel of sperm, the pHsensitive cationic channel of sperm (CatSper), result in complete male infertility without other detected defects in phenotype (3)(4)(5)(6)(8)(9)(10)(11)(12)(13)(14)(15). The absence of CatSper channels was shown to cause male infertility in mice (6,10,14), primarily because of an inability of sperm to hyperactivate (4,5).…”

mentioning

confidence: 99%

Disruption of the principal, progesterone-activated sperm Ca ²⁺ channel in a CatSper2-deficient infertile patient

Smith

Syritsyna

Fellous

et al. 2013

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

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151

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The female steroid hormone progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca 2+ leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that progesterone-dependent Ca 2+ influx into human spermatozoa is primarily mediated by cationic channel of sperm (CatSper), the principal flagellar Ca 2+ channel of sperm, conclusive loss-of-function genetic evidence for activation of CatSper by progesterone has yet to be provided. Moreover, it is not clear whether the responsiveness of CatSper to progesterone is an innate property of human spermatozoa or is acquired as the result of exposure to the seminal plasma. Here, by recording ionic currents from spermatozoa of an infertile CatSper-deficient patient, we demonstrate that CatSper is indeed the principal Ca 2+ channel of human spermatozoa, and that it is strongly potentiated by progesterone. In addition, by recording CatSper currents from human epididymal and testicular spermatozoa, we show that CatSper sensitivity to progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated. These results unambiguously establish an important role of CatSper channel in human sperm nongenomic progesterone signaling and demonstrate that the molecular mechanism responsible for activation of CatSper by progesterone arises early in sperm development concurrently with the CatSper channel itself.CatSper ion channel | male fertility | nongenomic steroid action | sperm physiology

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Genetic male infertility and mutation of CATSPER ion channels

Cited by 117 publications

References 43 publications

Flagellar ion channels of sperm: similarities and differences between species

Flagellar ion channels of sperm: similarities and differences between species

ATP-activated P2X2 current in mouse spermatozoa

Disruption of the principal, progesterone-activated sperm Ca ²⁺ channel in a CatSper2-deficient infertile patient

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Genetic male infertility and mutation of CATSPER ion channels

Cited by 117 publications

References 43 publications

Flagellar ion channels of sperm: similarities and differences between species

Flagellar ion channels of sperm: similarities and differences between species

ATP-activated P2X2 current in mouse spermatozoa

Disruption of the principal, progesterone-activated sperm Ca 2+ channel in a CatSper2-deficient infertile patient

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Disruption of the principal, progesterone-activated sperm Ca ²⁺ channel in a CatSper2-deficient infertile patient