Affinage

Showing CATSPER1 — CATSPER is a alias.

CATSPER1

Cation channel sperm-associated protein 1 · UniProt Q8NEC5

Length
780 aa
Mass
90.1 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CATSPER1 is the essential pore-forming subunit of the sperm-specific Ca2+ channel (CatSper) that drives the Ca2+ influx required for hyperactivated motility and fertilization (PMID:14657352, PMID:38165034). Genetic ablation of CatSper1 abolishes depolarization-evoked Ca2+ entry and hyperactivated motility while leaving general capacitation signaling intact, and re-expression of EGFP-CatSper1 rescues capacitation-associated Ca2+ influx (PMID:14657352, PMID:19860887). The functional channel is a heteromeric assembly: CatSper1 and CatSper2 are co-dependent for protein stability, all four pore subunits (CatSper1–4) physically associate and are jointly required for the CatSper current, and CatSper1 governs trafficking and stability of auxiliary transmembrane subunits CatSperβ, CatSperγ, CATSPERδ, and CATSPERθ to the principal piece of the flagellum (PMID:16036917, PMID:17227845, PMID:17478420, PMID:19516020, PMID:21224844, PMID:37725640). CatSper carries a mono- and divalent cation current that is gated by intracellular alkalinization, which depends on Na+/H+ exchanger-mediated flagellar pH homeostasis and on bicarbonate/soluble adenylyl cyclase/PKA-dependent sensitization (PMID:21412338, PMID:38366201, PMID:34650979, PMID:30213858). Together with the K+ channel Slo3 (KSper), CatSper constitutes the entirety of the alkalinization- and voltage-activated ion conductance of sperm (PMID:23980198). The channel functions as a polymodal chemosensor: progesterone, prostaglandins, odorants, the endocrine disruptor p,p'-DDE, and cAMP analogues activate human CatSper directly through extracellular binding sites rather than through metabotropic intracellular signaling, with steroids and prostaglandins acting at distinct shared sites and Zn2+ suppressing this activation (PMID:21412338, PMID:22354039, PMID:34381781, PMID:24067601, PMID:32703901). Through these inputs CatSper generates membrane-potential-coupled [Ca2+]i oscillations and controls swim-path chirality, penetration of viscous media and the egg coat, and progesterone-triggered release from the oviductal reservoir (PMID:33305795, PMID:35438819, PMID:23344959, PMID:31862909). In humans, frameshift mutations in CATSPER1 and loss of CatSper function cause autosomal-recessive nonsyndromic male infertility, with affected sperm failing to hyperactivate and penetrate the egg coat (PMID:19344877, PMID:38165034, PMID:26453676).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2003 High

    Established CatSper1 as a non-redundant determinant of sperm Ca2+ entry, distinguishing it from canonical voltage-gated Ca2+ channels and linking it specifically to hyperactivation.

    Evidence CatSper1 knockout mouse with Ca2+ imaging, motility analysis, and immunoblotting of CaV channels

    PMID:14657352

    Open questions at the time
    • Did not resolve the channel's subunit composition
    • Did not define the gating stimulus
  2. 2005 High

    Showed CatSper1 and CatSper2 are mutually required for protein stability, revealing the channel is an obligate multi-subunit assembly rather than an independent pore.

    Evidence CatSper1 and CatSper2 knockout mice with reciprocal Western blots and shared phenotypes

    PMID:16036917

    Open questions at the time
    • Did not establish full subunit stoichiometry
    • Mechanism of co-dependent stability not defined
  3. 2006 Medium

    Provided early evidence that CatSper1 physically associates with and modulates the T-type channel CaV3.3 in sperm, though this interaction was later superseded by the heterotetrameric CatSper model.

    Evidence Co-IP, heterologous electrophysiology, and FRET in human sperm and transfected cells

    PMID:16740636

    Open questions at the time
    • Functional relevance of CaV3.3 modulation in vivo unresolved
    • Single lab; not integrated into the core channel model
  4. 2007 High

    Defined the heterotetrameric pore as requiring all four CatSper subunits and identified CatSperβ as a CatSper1-dependent auxiliary subunit, building the architecture of the channel complex.

    Evidence CatSper3/4 knockout mice, patch-clamp, Co-IP, and affinity purification/MS from testis

    PMID:17227845 PMID:17478420

    Open questions at the time
    • Functional role of CatSperβ beyond trafficking unresolved
    • Stoichiometry within the tetramer not quantified
  5. 2009 High

    Extended the auxiliary subunit roster (CatSperγ) and tied CatSper to the BSA-induced capacitation Ca2+ influx via genetic rescue, and identified frameshift CATSPER1 mutations as a human male infertility cause.

    Evidence CatSper1 KO sperm with Co-IP/localization, EGFP-CatSper1 rescue, and autozygosity mapping in consanguineous families

    PMID:19344877 PMID:19516020 PMID:19860887

    Open questions at the time
    • Human mutations not validated by patient electrophysiology
    • Assembly mechanism of auxiliary subunits unresolved
  6. 2011 High

    Identified CatSper as the direct non-genomic progesterone receptor in human sperm and added CATSPERδ as an essential subunit, recasting CatSper as a ligand-gated ionotropic sensor.

    Evidence Whole-cell patch-clamp on human sperm with near-zero latency progesterone response; CATSPERδ KO mouse electrophysiology and fertility

    PMID:21224844 PMID:21412338

    Open questions at the time
    • Exact progesterone binding site on CatSper vs associated protein not localized
    • Structural basis of ligand gating undefined
  7. 2012 High

    Generalized the ionotropic mechanism by showing odorants and extracellular cAMP analogues activate CatSper through external binding sites, establishing it as a polymodal chemosensor independent of GPCR/cAMP cascades.

    Evidence Ca2+ fluorimetry and patch-clamp with Gs and adenylate cyclase inhibitors on human sperm

    PMID:22354039

    Open questions at the time
    • Molecular identity of the extracellular ligand sites unresolved
    • Physiological ligands for odorant responses unknown
  8. 2013 High

    Delineated CatSper's functional outputs and ion-channel context: CatSper and Slo3 are the sole alkalinization/voltage-gated conductances, CatSper promotes viscous-medium penetration distinct from store-driven hyperactivation, and the disruptor p,p'-DDE activates the channel.

    Evidence Slo3/CatSper1 double-KO patch-clamp, methylcellulose penetration with NNC55-0396, and electrophysiology of DDE on human sperm; plus CATSPER1 promoter mapping

    PMID:23313885 PMID:23344959 PMID:23980198 PMID:24067601

    Open questions at the time
    • Relationship between CatSper Ca2+ and store-driven hyperactivation not fully reconciled
    • In vivo significance of DDE activation unknown
  9. 2015 Medium

    Provided direct human evidence that CatSper function is required for fertilization and identified CRISP1 as a cumulus-derived modulator of CatSper current.

    Evidence Patch-clamp and IVF outcome in a CatSper-deficient man; patch-clamp plus CRISP1 KO mouse fertility

    PMID:26416967 PMID:26453676

    Open questions at the time
    • Human evidence rests on a single patient
    • Mechanism of CRISP1 modulation of the channel undefined
  10. 2017 Medium

    Implicated CCR6 as a physically associated mediator of ligand-induced CatSper activation in human sperm.

    Evidence Co-IP, co-localization, siRNA knockdown, Ca2+ imaging, and patch-clamp

    PMID:29207656

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Whether CCR6 binds ligands or acts structurally is unclear
  11. 2018 High

    Resolved the upstream regulatory logic by showing bicarbonate/cAMP/PKA-dependent phosphorylation up-regulates mouse CatSper and that CREB1/CREMτ drive CATSPER1 transcription.

    Evidence Patch-clamp with intrapipette cAMP and PKA inhibitors plus CatSper1 KO; CRE-site mutagenesis luciferase assays

    PMID:30017233 PMID:30213858

    Open questions at the time
    • Direct PKA phosphosite on CatSper not mapped
    • Species generality of PKA regulation not yet addressed
  12. 2020 High

    Revised the regulatory model for human sperm by demonstrating cAMP does not gate human CatSper intracellularly and that common PKA inhibitors are off-target direct channel blockers, sharpening interpretation of pharmacological studies.

    Evidence Ion-sensitive fluorometry, patch-clamp, optochemistry, and CatSper-deficient patient sperm

    PMID:32703901

    Open questions at the time
    • Reconciliation with mouse PKA sensitization not fully resolved
    • Physiological extracellular cAMP source undefined
  13. 2021 High

    Integrated the gating circuitry and ligand pharmacology: NHE-dependent pH homeostasis and bicarbonate/sAC/PKA prime CatSper, membrane-potential feedback generates [Ca2+]i oscillations, steroids and prostaglandins act at distinct shared sites suppressed by Zn2+, Cdc42 supports channel function via sAC, and CatSper mediates progesterone-driven oviductal release.

    Evidence Patch-clamp, current-clamp, Ca2+ imaging, structure-activity analysis on CATSPER2-deficient sperm, Cdc42 inhibition with KO localization, and oviduct release assays

    PMID:31862909 PMID:33305795 PMID:34224609 PMID:34381781 PMID:34650979

    Open questions at the time
    • Atomic structure of steroid/prostaglandin sites unresolved
    • Direct vs indirect role of Cdc42 partially pharmacological
  14. 2022 High

    Expanded the complex with the C2-domain subunit C2CD6 and showed CatSper and its Ca2+ sensor EFCAB9 control swim-path chirality, linking channel assembly and Ca2+ sensing to flagellar steering behavior.

    Evidence C2CD6 KO with Co-IP, patch-clamp, fertility and ionophore rescue; CatSper/EFCAB9 KO motility path analysis

    PMID:34919125 PMID:35438819

    Open questions at the time
    • Mechanism linking Ca2+ flux to chirality unresolved
    • EFCAB9 Ca2+-sensing details in path control incomplete
  15. 2023 High

    Identified CATSPERθ as an assembly scaffold for CATSPER4 and the CatSper dimer interface, completing a structural picture in which transmembrane subunit loss collapses the whole channel during spermatogenesis.

    Evidence CATSPERθ KO mouse with Co-IP, immunofluorescence, cross-KO protein analysis, and fertility/motility assays

    PMID:37725640

    Open questions at the time
    • Stoichiometric model of the dimer not fully resolved
    • Translational control via CUG initiation not mechanistically explored
  16. 2024 High

    Provided large-cohort human evidence that CatSper-dependent hyperactivation is required for egg-coat penetration and natural fertilization, and identified seminal-plasma extracellular vesicles as physiological CatSper activators.

    Evidence Motility-based CatSper test in ~2,300 men with patch-clamp, gene sequencing, and ICSI outcomes; EV potentiation of CatSper with patient KO controls and proteomics

    PMID:38165034 PMID:38335261

    Open questions at the time
    • Active EV ligand(s) and their binding sites unresolved
    • Genotype-phenotype spectrum across CATSPER genes incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The atomic-resolution structural basis of how diverse extracellular ligands and pH/voltage inputs gate the assembled CatSper complex, and the molecular identity of the multiple ligand-binding sites, remain unresolved.
  • No structural model of ligand-bound channel in the timeline
  • Binding sites for progesterone, prostaglandins, odorants, and EV components not localized at residue level

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 3
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3
Partners
C2CD6CACNA1ICATSPER2CATSPER3CATSPER4CATSPERDCCR6EFCAB9
Complex memberships
CatSper channel complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CatSper1 is essential for depolarization-evoked Ca2+ entry and hyperactivated motility in mouse sperm flagella; CatSper1 null sperm lack depolarization-evoked Ca2+ influx but retain normal capacitation signaling (cAMP-mediated motility activation, protein phosphorylation cascade) and normal distribution of CaV1.2, CaV2.2, and CaV2.3 proteins. CatSper1 knockout mouse model; Ca2+ imaging; sperm motility analysis; Western blot/immunofluorescence for other Ca2+ channel proteins Proceedings of the National Academy of Sciences of the United States of America High 14657352
2005 Stable expression of CatSper1 protein requires CatSper2 and vice versa: CatSper1 null sperm lack CatSper2 protein and CatSper2 null sperm lack CatSper1 protein, indicating co-dependent protein stability. Both null phenotypes share identical loss of depolarization-evoked Ca2+ entry and hyperactivated motility. CatSper1 and CatSper2 knockout mouse models; Western blot for co-dependent protein levels; Ca2+ imaging; sperm motility analysis The Journal of biological chemistry High 16036917
2007 All four CatSper proteins (CatSper1–4) are required to form the functional sperm-specific Ca2+ current (ICatSper); targeted disruption of CatSper3 or CatSper4 abrogates ICatSper, hyperactivated motility, and male fertility. Direct protein interactions among the four CatSper subunits were demonstrated, consistent with a heterotetrameric channel. CatSper3 and CatSper4 knockout mice; patch-clamp electrophysiology; co-immunoprecipitation; sperm motility analysis; fertility assays Proceedings of the National Academy of Sciences of the United States of America High 17227845
2007 CatSperβ (a novel two-transmembrane domain protein) is an auxiliary subunit of the CatSper channel complex; it was co-purified with CatSper1 from mouse testis, is testis-specific, localizes to the sperm principal piece, and is absent in CatSper1-null sperm, indicating CatSper1-dependent trafficking/stability. CatSper1 transgenic complex purification from mouse testis; mass spectrometry identification; Western blot in CatSper1 KO sperm; immunolocalization The Journal of biological chemistry High 17478420
2009 CatSperγ (a single-transmembrane protein with large extracellular domain) associates with the CatSper channel complex; it is testis-specific, localizes to the sperm principal piece, and its protein level is lost in CatSper1-deficient sperm, indicating CatSper1-dependent assembly/trafficking. The K+ channel KCNU1 is not lost in CatSper1-null sperm, demonstrating specificity. Co-immunoprecipitation/Western blot; CatSper1 KO sperm analysis; immunolocalization Biology of reproduction High 19516020
2009 The BSA-induced fast-phase Ca2+ influx during sperm capacitation requires the CatSper channel: it is absent in CatSper1 KO sperm and restored by an EGFP-CatSper1 fusion protein. The Ca2+ increase is independent of G-proteins and phospholipase C but is partially pH-dependent, and it initiates in the principal piece and propagates toward the sperm head. CatSper1 knockout mouse sperm; Fluo-4/Fura-2 Ca2+ imaging; EGFP-CatSper1 rescue; pharmacological inhibitors of G-proteins and PLC Reproductive biology and endocrinology High 19860887
2011 Progesterone directly activates the CatSper Ca2+ channel in human sperm, stimulating a rapid Ca2+ influx and enhancing CatSper patch-clamp current with near-zero latency incompatible with metabotropic signaling. The CatSper current is carried by mono- and divalent ions, is activated by alkaline pH, and is blocked by NNC 55-0396 and mibefradil. CatSper itself or an associated protein functions as the non-genomic progesterone receptor. Whole-cell patch-clamp electrophysiology on human sperm; Ca2+ fluorimetry; pharmacological inhibitors (NNC 55-0396, mibefradil) Nature High 21412338
2011 CATSPERδ (encoded by Tmem146) is an essential subunit of the CatSper channel complex required for CatSper Ca2+ current and hyperactivated motility; CATSPERδ-null mice are infertile and their sperm lack both ICatSper and hyperactivation. CATSPERδ is proposed to be required for proper channel assembly and/or transport to the sperm tail. CATSPERδ (Tmem146) knockout mouse; patch-clamp electrophysiology; sperm motility analysis; fertility assay; co-immunoprecipitation Nature communications High 21224844
2012 CatSper in human sperm functions as a polymodal chemosensor: odorants directly activate CatSper without involving GPCRs or cAMP, and membrane-permeable cAMP analogues activate CatSper via an extracellular binding site rather than through intracellular cAMP signaling pathways. Ca2+ fluorimetry; patch-clamp electrophysiology; pharmacological dissection (Gs inhibitors, adenylate cyclase inhibitors); comparison with progesterone responses The EMBO journal High 22354039
2006 CatSper1 and CatSper2 physically associate with the T-type voltage-gated Ca2+ channel CaV3.3 in human sperm; co-expression of CatSper1 or CatSper2 with CaV3.3 inhibits CaV3.3 T-type Ca2+ current amplitude without altering biophysical properties. CatSper1 and CaV3.3 co-localize on the sperm tail principal piece and show close physical proximity by FRET. Co-immunoprecipitation from human sperm and transfected mammalian cells; electrophysiology (patch-clamp) in heterologous expression; immunostaining; FRET analysis; multidimensional protein identification technology (MudPIT) The Journal of biological chemistry Medium 16740636
2013 CatSper and intracellular Ca2+ stores regulate distinct sperm behaviors: CatSper activation (by pH elevation or progesterone) causes sustained Ca2+ elevation and enhances penetration into viscous medium but does not induce hyperactivation, whereas Ca2+ mobilization from stores induces hyperactivation independently of CatSper (insensitive to NNC55-0396). Ca2+ fluorimetry; methylcellulose penetration assay; NNC55-0396 pharmacological inhibition; thimerosal-induced Ca2+ store mobilization; computer-assisted sperm analysis The Journal of biological chemistry Medium 23344959
2013 Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization-activated and voltage-activated ion current in mouse sperm, demonstrating that CatSper and KSPER (Slo3) are the sole ion channels regulating membrane potential and Ca2+ influx in response to alkalization in mouse sperm. Double knockout mice (Slo3-/-; CatSper1-/-); patch-clamp electrophysiology The Journal of general physiology High 23980198
2014 In Arbacia punctulata sea urchin sperm, CatSper channels mediate chemoattractant-evoked Ca2+ influx and control chemotactic steering; concomitant flagellar alkalinization serves as a cooperative mechanism enabling CatSper to transduce periodic voltage changes into Ca2+ bursts. Ca2+ imaging; electrophysiology; pharmacological inhibition; chemoattractant stimulation assays The EMBO journal High 25535245
2015 CRISP1 (a protein expressed by cumulus cells surrounding the egg) modulates CatSper channel activity in mouse sperm, as demonstrated by patch-clamp recordings showing CRISP1-mediated regulation of CatSper current; CRISP1 stimulates sperm hyperactivation and orientation for penetration of the cumulus. Whole-cell patch-clamp electrophysiology; CRISP1 KO mouse fertility assay; sperm motility analysis The Journal of cell biology Medium 26416967
2018 CatSper channels in mouse sperm are up-regulated by PKA-dependent phosphorylation downstream of bicarbonate/cAMP: HCO3- and 8-Br-cAMP increase CatSper activity, effects blocked by PKA inhibitors (PKI, H89, Rp-cAMPS) and the CatSper blocker HC-056456. Direct cAMP injection through the patch-clamp pipette also up-regulated CatSper current. CatSper KO mice confirmed channel identity. Patch-clamp electrophysiology with intrapipette cAMP injection; Ca2+ imaging; monovalent cation influx assay; PKA inhibitors; CatSper1 KO mouse confirmation The Journal of biological chemistry High 30213858
2018 RU1968 is a cross-species CatSper inhibitor that blocks CatSper in human, mouse, and sea urchin sperm; it lacks toxic side effects on human sperm, does not affect mouse Slo3, and inhibits human Slo3 with ~15-fold lower potency than CatSper. In human sperm it suppresses progesterone-evoked motility responses and abolishes CatSper-mediated chemotactic navigation in sea urchin. Ca2+ fluorimetry; single-cell Ca2+ imaging; whole-cell patch-clamp electrophysiology; optochemistry; motility analysis British journal of pharmacology High 29723408
2020 Human CatSper is not activated by intracellular cAMP directly or indirectly via the cAMP/PKA pathway. Instead, non-physiological concentrations of cAMP and membrane-permeable cAMP analogs activate human CatSper from the outside via a previously unknown extracellular binding site. Common PKA inhibitors (H89, Rp-cAMPS) act predominantly as off-target direct blockers of CatSper rather than inhibitors of PKA. CatSper-deficient patient sperm confirmed channel identity. Kinetic ion-sensitive fluorometry; patch-clamp electrophysiology; optochemistry; CatSper-deficient patient sperm as negative control The Journal of biological chemistry High 32703901
2021 Progesterone-induced [Ca2+]i oscillations in human sperm are generated in the flagellum by membrane potential-sensitive Ca2+ influx through CatSper channels; hyperpolarization with valinomycin suppresses oscillations and the CatSper inhibitor RU1968 reversibly arrests oscillations in a dose-dependent manner. Quinidine (IKsper blocker) also inhibits oscillations, implicating a Vm feedback loop. Single-cell Ca2+ fluorescence imaging; whole-cell current-clamp electrophysiology; pharmacological inhibitors (valinomycin, RU1968, quinidine) Human reproduction High 33305795
2021 Cdc42 co-localizes with CatSper in the principal piece of mouse sperm flagella in a CatSper1-dependent manner (localization disrupted in CatSper1-null sperm). Cdc42 inhibition impairs CatSper activity and downstream Ca2+-dependent events; Cdc42 regulates CatSper function by modulating cAMP production via soluble adenylate cyclase (sAC). CatSper1 KO sperm; Ca2+ imaging; patch-clamp electrophysiology; pharmacological Cdc42 inhibition; immunofluorescence co-localization FASEB journal Medium 34224609
2021 Bicarbonate in semen sensitizes CatSper channels via a conserved mechanism in both mouse and human sperm: HCO3- activates soluble adenylyl cyclase/PKA, raising intracellular pH, which sensitizes CatSper to respond to membrane depolarization. This mechanism is absent in epididymal sperm before ejaculation but is triggered by HCO3- pre-incubation. Ca2+ imaging with KCl depolarization in multiple conditions; PKA inhibitors; pH manipulation; comparison of epididymal vs. ejaculated sperm from both species Frontiers in cell and developmental biology Medium 34650979
2021 All steroids and prostaglandins present in reproductive fluids activate CatSper via shared binding sites: steroids compete for the same steroid-binding site and prostaglandins for the same prostaglandin-binding site on the channel. Zn2+ suppresses steroid- and prostaglandin-induced CatSper activation, potentially preventing premature activation in the ejaculate. Ca2+ fluorimetry comparing CATSPER2-deficient patient sperm vs. donor sperm; structure-activity relationship analysis of hormones; patch-clamp electrophysiology Frontiers in cell and developmental biology High 34381781
2022 C2CD6, a protein containing a calcium-dependent C2 domain, is a subunit of the mouse CatSper complex that associates with core pore-forming CatSper subunits and with EFCAB9. C2CD6 deficiency depletes CatSper nanodomains from the flagellum, reduces CatSper current amplitude, causes male infertility, and impairs hyperactivation. Ca2+ ionophore treatment or starvation restores fertilization capacity of C2CD6-deficient sperm. Co-immunoprecipitation; C2CD6 KO mouse; patch-clamp electrophysiology; in vitro and in vivo fertility assays; immunofluorescence; Ca2+ ionophore rescue Development (Cambridge, England) High 34919125
2022 CatSper path chirality in mouse sperm depends on CatSper channel function and its Ca2+ sensor EFCAB9: sperm lacking the entire CatSper channel or EFCAB9 lose clockwise swim path chirality, and pharmacological CatSper inhibitors (mibefradil, NNC 55-0396) replicate this loss. Zona pellucida glycoprotein ZP2 randomizes chirality only in capacitated cells. CatSper KO and EFCAB9 KO mouse sperm; pharmacological inhibition; motility path analysis; ZP2 stimulation FASEB journal Medium 35438819
2023 CATSPERθ (encoded by Tmem249, initiated by a CUG codon) is a transmembrane subunit required for CatSper channel assembly during sperm tail formation; it serves as a scaffold for CATSPER4, self-interacts suggesting a role in CatSper dimer formation, and localizes at the interface of CatSper dimers. CATSPERθ-null male mice are infertile because the entire CatSper channel is absent from sperm flagella. Genetic abrogation of other CatSper TM subunits causes loss of CATSPERθ protein during spermatogenesis. CATSPERθ (Tmem249) KO mouse; co-immunoprecipitation; immunofluorescence; fertility assay; motility analysis; cross-KO protein expression analysis Proceedings of the National Academy of Sciences of the United States of America High 37725640
2024 CatSper-deficient human sperm are unable to undergo hyperactivated motility and fail to penetrate the egg coat, causing fertilization failure that requires ICSI for conception. CatSper deficiency was caused by variants in CATSPER genes. This constitutes direct experimental evidence that sperm hyperactivation requires CatSper and is necessary for human fertilization. Motility-based CatSper functional test in ~2,300 men; patch-clamp electrophysiology; IVF/IUI outcomes; ICSI rescue; CATSPER gene sequencing; egg coat penetration assay The Journal of clinical investigation High 38165034
2009 Frameshift insertion mutations in CATSPER1 (c.539-540insT and c.948-949insATGGC) cause autosomal-recessive nonsyndromic male infertility in humans, establishing CATSPER1 as an essential human male fertility factor. Autozygosity mapping; DHPLC; bidirectional sequencing in consanguineous families American journal of human genetics Medium 19344877
2013 The CATSPER1 promoter lacks a TATA box and contains a conserved CRE site; it exhibits transcriptional activity in both orientations. Transcription factor binding sites for SRY, SOX9, and CREB are protected by testicular nuclear proteins in DNase I footprinting, and suppression of the promoter reduces CatSper1 expression in mouse testis in vivo. Promoter cloning; luciferase reporter assays in multiple cell lines; RNA ligase-mediated RACE; DNase I footprinting; plasmid injection into mouse testes Molecular human reproduction Medium 23313885
2018 CREB1 and CREMτ transcription factors positively regulate CATSPER1 promoter activity in vitro; CRE0 site is required for basal transcriptional activity in spermatogonial cells, while CRE1 site suppresses activity. CREB-A and CREMτ synergistically enhance CATSPER1 promoter activity in HEK293 cells. Dual-luciferase reporter assays; site-directed CRE deletion mutagenesis; transient transfection in HEK293 and GC1-spg cells Archives of medical research Medium 30017233
2015 Specific loss of CatSper function (near-absence of CatSper current by patch-clamp) in a man with normal semen parameters causes failure to respond to progesterone, failure to penetrate viscous media, and fertilization failure at IVF, providing direct evidence that CatSper function is required for human fertilization. Whole-cell patch-clamp electrophysiology; Ca2+ imaging; methylcellulose penetration assay; IVF outcome data; CATSPER gene exon screening Human reproduction Medium 26453676
2013 p,p'-DDE (an endocrine disruptor) activates CatSper channels in human sperm, increasing CatSper current by >100% as confirmed by whole-cell patch-clamp, causing Ca2+ influx even at picomolar concentrations. CatSper inhibitors (mibefradil, NNC 55-0396) reverse the effect. Whole-cell patch-clamp electrophysiology; Ca2+ single-cell imaging; CatSper inhibitor pharmacology; low Ca2+ medium controls Human reproduction Medium 24067601
2019 Progesterone-stimulated release of sperm from oviduct cells/immobilized glycan requires CatSper: blocking CatSper with NNC 055-0396 abolishes both the progesterone-induced Ca2+ influx and sperm release. An inhibitor of the non-genomic progesterone receptor that activates CatSper similarly blocked sperm release. Sperm-oviduct cell aggregate binding/release assay; Ca2+ imaging; CatSper pharmacological inhibition; NNC 055-0396 Scientific reports Medium 31862909
2017 CCR6 (C-C chemokine receptor 6) co-localizes and physically interacts with CatSper in human sperm. Both CCR6 and CatSper are required for Ca2+ entry and current induced by DEFB1, CCL20, and progesterone. Knockdown of CCR6 reduces CatSper-mediated Ca2+ influx, implicating CCR6 as a mediator of ligand-induced CatSper activation. Co-immunoprecipitation; immunofluorescence co-localization; Ca2+ imaging; patch-clamp electrophysiology; siRNA knockdown Oncotarget Medium 29207656
2022 TET1 regulates CatSper1–4 expression through DNA hydroxymethylation: TET1 overexpression promotes hydroxymethylation (5hmC) of CatSper1–4 loci, reduces methylation, and increases their expression, while TET1 knockdown has the opposite effect. BPA reduces TET1 expression and consequently CatSper1–4 expression and intracellular Ca2+ in GC-2 spermatogonial cells. TET1 overexpression and knockdown in GC-2 cells; 5hmC/5mC quantification; Western blot; Ca2+ measurement Environmental pollution Low 34953956
2021 NHE-mediated flagellar intracellular pH homeostasis is required for CatSper and KSper activation in human sperm: NHE inhibition by DMA severely acidifies flagellar pHi and markedly suppresses alkalization-induced CatSper and KSper currents as measured by patch-clamp, impairing Ca2+ homeostasis and multiple capacitation-dependent functions. Whole-cell patch-clamp electrophysiology; pHi fluorimetry (pHrodo Red-AM); Ca2+ imaging; membrane potential measurement; DMA pharmacological inhibition Human reproduction High 38366201
2024 Seminal plasma extracellular vesicles (EVs) activate CatSper channels in human sperm, increasing intracellular Ca2+ via extracellular Ca2+ influx: EVs potentiate CatSper currents, and CatSper-deficient sperm show absent EV-induced Ca2+ increases. Both protein and non-protein EV components contribute to CatSper activation and subsequent sperm hyperactivated motility. Patch-clamp electrophysiology; Ca2+ fluorimetry; CatSper-deficient patient sperm; CatSper inhibitor; CASA motility analysis; LC-MS proteomics of EV components Human reproduction High 38335261

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 437 21412338
2007 All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proceedings of the National Academy of Sciences of the United States of America 412 17227845
2003 CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm. Proceedings of the National Academy of Sciences of the United States of America 299 14657352
2012 The CatSper channel: a polymodal chemosensor in human sperm. The EMBO journal 186 22354039
2009 Human male infertility caused by mutations in the CATSPER1 channel protein. American journal of human genetics 172 19344877
2011 A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa. Nature communications 168 21224844
2010 The role of Hv1 and CatSper channels in sperm activation. The Journal of physiology 151 20679352
2005 Identical phenotypes of CatSper1 and CatSper2 null sperm. The Journal of biological chemistry 145 16036917
2007 CatSperbeta, a novel transmembrane protein in the CatSper channel complex. The Journal of biological chemistry 133 17478420
2013 Ca2+ signals generated by CatSper and Ca2+ stores regulate different behaviors in human sperm. The Journal of biological chemistry 123 23344959
2010 Genetic male infertility and mutation of CATSPER ion channels. European journal of human genetics : EJHG 116 20648059
2014 The CatSper calcium channel in human sperm: relation with motility and involvement in progesterone-induced acrosome reaction. Human reproduction (Oxford, England) 104 24430778
2009 A novel, single, transmembrane protein CATSPERG is associated with CATSPER1 channel protein. Biology of reproduction 99 19516020
2009 The BSA-induced Ca2+ influx during sperm capacitation is CATSPER channel-dependent. Reproductive biology and endocrinology : RB&E 98 19860887
2014 CatSper channel, sperm function and male fertility. Reproductive biomedicine online 96 25457194
2014 The CatSper channel controls chemosensation in sea urchin sperm. The EMBO journal 79 25535245
2015 Specific loss of CatSper function is sufficient to compromise fertilizing capacity of human spermatozoa. Human reproduction (Oxford, England) 77 26453676
2015 CRISP1 as a novel CatSper regulator that modulates sperm motility and orientation during fertilization. The Journal of cell biology 73 26416967
2007 Expression of CatSper family transcripts in the mouse testis during post-natal development and human ejaculated spermatozoa: relationship to sperm motility. Molecular human reproduction 69 17347248
2013 CatSper and the relationship of hyperactivated motility to intracellular calcium and pH kinetics in equine sperm. Biology of reproduction 66 24048572
2013 p,p'-DDE activates CatSper and compromises human sperm function at environmentally relevant concentrations. Human reproduction (Oxford, England) 63 24067601
2018 A novel cross-species inhibitor to study the function of CatSper Ca2+ channels in sperm. British journal of pharmacology 61 29723408
2018 CatSper channels are regulated by protein kinase A. The Journal of biological chemistry 61 30213858
2017 Exposure to Cadmium Impairs Sperm Functions by Reducing CatSper in Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 55 28554186
2013 Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa. The Journal of general physiology 48 23980198
2018 Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity. Human reproduction (Oxford, England) 46 30239785
2015 Progesterone Accelerates the Completion of Sperm Capacitation and Activates CatSper Channel in Spermatozoa from the Rhesus Macaque. Biology of reproduction 42 26490839
2021 Roles of CatSper channels in the pathogenesis of asthenozoospermia and the therapeutic effects of acupuncture-like treatment on asthenozoospermia. Theranostics 41 33456575
2020 The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA. The Journal of biological chemistry 41 32703901
2013 Levels of Tektin 2 and CatSper 2 in normozoospermic and oligoasthenozoospermic men and its association with motility, fertilization rate, embryo quality and pregnancy rate. Journal of assisted reproduction and genetics 41 23519396
2009 Up-regulation of CatSper genes family by selenium. Reproductive biology and endocrinology : RB&E 41 19917098
2005 Positive selection for indel substitutions in the rodent sperm protein catsper1. Molecular biology and evolution 41 15930155
2019 Release of Porcine Sperm from Oviduct Cells is Stimulated by Progesterone and Requires CatSper. Scientific reports 40 31862909
2016 Bisphenol A Impairs Mature Sperm Functions by a CatSper-Relevant Mechanism. Toxicological sciences : an official journal of the Society of Toxicology 40 27125968
2016 Diethylstilbestrol activates CatSper and disturbs progesterone actions in human spermatozoa. Human reproduction (Oxford, England) 39 28031325
2024 Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation. The Journal of clinical investigation 34 38165034
2015 Quantification of CatSper1 expression in human spermatozoa and relation to functional parameters. Human reproduction (Oxford, England) 32 25983333
2017 Complex CatSper-dependent and independent [Ca2+]i signalling in human spermatozoa induced by follicular fluid. Human reproduction (Oxford, England) 27 28938737
2019 Comparative genomic analysis suggests that the sperm-specific sodium/proton exchanger and soluble adenylyl cyclase are key regulators of CatSper among the Metazoa. Zoological letters 26 31372239
2017 Genomic identification, expression profiling, and functional characterization of CatSper channels in the bovine. Biology of reproduction 26 29044427
2022 C2CD6 regulates targeting and organization of the CatSper calcium channel complex in sperm flagella. Development (Cambridge, England) 24 34919125
2021 Conserved Mechanism of Bicarbonate-Induced Sensitization of CatSper Channels in Human and Mouse Sperm. Frontiers in cell and developmental biology 24 34650979
2021 [Ca2+]i oscillations in human sperm are triggered in the flagellum by membrane potential-sensitive activity of CatSper. Human reproduction (Oxford, England) 23 33305795
2020 Pentachlorophenol inhibits CatSper function to compromise progesterone's action on human sperm. Chemosphere 23 32622245
2021 Pharmacological Inactivation of CatSper Blocks Sperm Fertilizing Ability Independently of the Capacitation Status of the Cells: Implications for Non-hormonal Contraception. Frontiers in cell and developmental biology 22 34295893
2018 Effects of pH manipulation, CatSper stimulation and Ca2+-store mobilization on [Ca2+]i and behaviour of human sperm. Human reproduction (Oxford, England) 22 30239776
2021 Cdc42 localized in the CatSper signaling complex regulates cAMP-dependent pathways in mouse sperm. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 34224609
2017 Chromatin Protamination and Catsper Expression in Spermatozoa Predict Clinical Outcomes after Assisted Reproduction Programs. Scientific reports 21 29123209
2011 Immunization of male mice with B-cell epitopes in transmembrane domains of CatSper1 inhibits fertility. Fertility and sterility 21 22196715
2006 The expression and significance of CATSPER1 in human testis and ejaculated spermatozoa. Asian journal of andrology 21 16625279
2023 A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking. Proceedings of the National Academy of Sciences of the United States of America 20 37725640
2017 Network model predicts that CatSper is the main Ca2+ channel in the regulation of sea urchin sperm motility. Scientific reports 20 28652586
2017 CCR6 is required for ligand-induced CatSper activation in human sperm. Oncotarget 20 29207656
2013 Effects of Vitamin-E treatment on CatSper genes expression and sperm quality in the testis of the aging mouse. Iranian journal of reproductive medicine 20 24639725
2021 CRISP2, CATSPER1 and PATE1 Expression in Human Asthenozoospermic Semen. Cells 19 34440724
2012 Down-regulation of CatSper1 channel in epididymal spermatozoa contributes to the pathogenesis of asthenozoospermia, whereas up-regulation of the channel by Sheng-Jing-San treatment improves the sperm motility of asthenozoospermia in rats. Fertility and sterility 19 23148924
2019 Inhibition of CatSper and Hv1 Channels and NOX5 Enzyme Affect Progesterone-Induced Increase of Intracellular Calcium Concentration and ROS Generation in Human Sperm. Iranian journal of medical sciences 18 30936599
2019 Expression Analysis of the CRISP2, CATSPER1, PATE1 and SEMG1 in the Sperm of Men with Idiopathic Asthenozoospermia. Journal of reproduction & infertility 18 31058050
2018 Inhibition of the CatSper Channel and NOX5 Enzyme Activity Affects the Functions of the Progesterone-Stimulated Human Sperm. Iranian journal of medical sciences 18 29398748
2014 Panax ginseng induces the expression of CatSper genes and sperm hyperactivation. Asian journal of andrology 17 24969054
2021 The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm. Frontiers in cell and developmental biology 16 34381781
2022 SOX11-dependent CATSPER1 expression controls colon cancer cell growth through regulation the PI3K/AKT signaling pathway. Genes & genomics 15 35305240
2019 The effect of clomiphene citrate and human chorionic gonadotropin on the expression of CatSper1, CatSper2, LHCGR, and SF1 genes, as well as the structural changes in testicular tissue of adult rats. Molecular reproduction and development 15 31041823
2017 Cryopreservation of cynomolgus macaque (Macaca fascicularis) sperm with glycerol and ethylene glycol, and its effect on sperm-specific ion channels - CatSper and Hv1. Theriogenology 15 28806626
2015 Analysis of the correlation of CATSPER single nucleotide polymorphisms (SNPs) with idiopathic asthenospermia. Journal of assisted reproduction and genetics 15 26354096
2022 In vitro investigation of endocrine disrupting effects of pesticides on Ca2+-signaling in human sperm cells through actions on the sperm-specific and steroid-activated CatSper Ca2+-channel. Environment international 14 35853389
2020 Does the Pre-Ovulatory Pig Oviduct Rule Sperm Capacitation In Vivo Mediating Transcriptomics of Catsper Channels? International journal of molecular sciences 14 32155986
2018 Alteration in CatSper1 and 2 genes expression, sperm parameters and testis histology in varicocelized rats. International journal of reproductive biomedicine 14 29766149
2018 Assessment of sperm morphology, chromatin integrity, and catSper genes expression in hypothyroid mice. Acta biologica Hungarica 14 30257580
2015 Construction of a catsper1 DNA vaccine and its antifertility effect on male mice. PloS one 14 25993432
2006 Association of Catsper1 or -2 with Ca(v)3.3 leads to suppression of T-type calcium channel activity. The Journal of biological chemistry 14 16740636
2024 Both protein and non-protein components in extracellular vesicles of human seminal plasma improve human sperm function via CatSper-mediated calcium signaling. Human reproduction (Oxford, England) 13 38335261
2021 Molecular Evolution of CatSper in Mammals and Function of Sperm Hyperactivation in Gray Short-Tailed Opossum. Cells 13 33946695
2023 High-throughput screening method for discovering CatSper inhibitors using membrane depolarization caused by external calcium chelation and fluorescent cell barcoding. Frontiers in cell and developmental biology 12 36743410
2022 Prevention of Testicular Damage by Indole Derivative MMINA via Upregulated StAR and CatSper Channels with Coincident Suppression of Oxidative Stress and Inflammation: In Silico and In Vivo Validation. Antioxidants (Basel, Switzerland) 12 36290786
2014 Correlation between expression of CatSper family and sperm profiles in the adult mouse testis following Iranian Kerack abuse. Andrology 12 24619711
2013 Molecular cloning and analysis of the Catsper1 gene promoter. Molecular human reproduction 12 23313885
2022 Human sperm cells can form paracetamol metabolite AM404 that directly interferes with sperm calcium signalling and function through a CatSper-dependent mechanism. Human reproduction (Oxford, England) 11 35259261
2022 Bicarbonate-Triggered In Vitro Capacitation of Boar Spermatozoa Conveys an Increased Relative Abundance of the Canonical Transient Receptor Potential Cation (TRPC) Channels 3, 4, 6 and 7 and of CatSper-γ Subunit mRNA Transcripts. Animals : an open access journal from MDPI 11 35454259
2020 Modular analysis of the control of flagellar Ca2+-spike trains produced by CatSper and CaV channels in sea urchin sperm. PLoS computational biology 11 32119665
2019 The CatSper channel is present and plays a key role in sperm motility of the Atlantic salmon (Salmo salar). Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 11 31841710
2018 Down-regulation of CatSper 1 and CatSper 2 genes by lead and mercury. Environmental toxicology and pharmacology 11 29549816
2017 Catsper1 promoter is bidirectional and regulates the expression of a novel lncRNA. Scientific reports 11 29042633
2024 Environmental pollutants and male infertility: Effects on CatSper. Ecotoxicology and environmental safety 10 38653022
2023 CatSper mediates not only chemotactic behavior but also the motility of ascidian sperm. Frontiers in cell and developmental biology 10 38020915
2021 Finasteride interferes with prostaglandin-induced CatSper signalling in human sperm. Reproduction (Cambridge, England) 10 33729179
2018 Human CATSPER1 Promoter Is Regulated by CREB1 and CREMτ Transcriptional Factors In Vitro. Archives of medical research 10 30017233
2011 Molecular cloning, spatial and temporal expression analysis of CatSper genes in the Chinese Meishan pigs. Reproductive biology and endocrinology : RB&E 10 21970684
2024 Flagellar pH homeostasis mediated by Na+/H+ exchangers regulates human sperm functions through coupling with CatSper and KSper activation. Human reproduction (Oxford, England) 9 38366201
2021 TET1 mediated male reproductive toxicity induced by Bisphenol A through Catsper-Ca2+ signaling pathway. Environmental pollution (Barking, Essex : 1987) 9 34953956
2019 Effect of selenium and pentoxifylline on expression of CATSPER1 and 2 genes and FSH/LH levels in treated mice by dexamethasone. Andrologia 9 30983026
2012 Sperm are promiscuous and CatSper is to blame…. The EMBO journal 9 22415366
2022 CatSper and its CaM-like Ca2+ sensor EFCAB9 are necessary for the path chirality of sperm. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 35438819
2021 CatSper channels in sea urchin sperm. Cell calcium 8 34509139
2014 Structural evolution of CatSper1 in rodents is influenced by sperm competition, with effects on sperm swimming velocity. BMC evolutionary biology 8 24884901
2008 CatSper genes expression, semen characteristics and histology of testes in the contusive spinal cord-injured mice model. Spinal cord 8 18607386
2022 Association of CATSPER1, SPATA16 and TEX11 genes polymorphism with idiopathic azoospermia and oligospermia risk in Iranian population. BMC medical genomics 7 35248021
2016 Cd(2+) sensitivity and permeability of a low voltage-activated Ca(2+) channel with CatSper-like selectivity filter. Cell calcium 7 27134080
2015 The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex. ACS chemical biology 7 26674547
2024 Sperm hyperactivation and the CatSper channel: current understanding and future contribution of domestic animals. Journal of animal science and technology 6 38975583

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