Nomenclature: CatSper1

Family: CatSper and Two-Pore channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 780 11q12.1 CATSPER1 cation channel, sperm associated 1 18
Mouse 6 1 686 19 A Catsper1 cation channel, sperm associated 1 18
Rat 6 1 684 1q43 Catsper1 cation channel, sperm associated 1
Previous and Unofficial Names
Names References
Cation channel of sperm 18
cation channel sperm-associated protein 1 18
CATSPER (human)
SPGF7 (human)
CatSper (mouse) 18
Database Links
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
CatSper3 8,14
CatSper4 8,14
CatSper2 14-17
Auxiliary Subunits
Name References
CatSperBeta 6,12
CatSperGamma 6,21
CatSperDelta 6
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
CatSper channels appear to function (i.e. produce the current known as ICatSper) only when all the known components form a complex including CatSper1-4 heterotetramer and the auxiliary subunits beta, gamma, and delta are present. The requirement for the presence of all subunits is confirmed by the observation that an identical phenotype is observed in any CatSper1, 2, 3, 4, or delta knock-out models. The stoichiometry of the auxiliary subunits to pore-forming alpha subunits CatSper1-4 is not known. Expression of CatSper subunits in mature spermatozoa is co-dependent.

In contrast to auxiliary subunits associated with other ion channels, which only modulate gating or trafficking of the channel pore, the auxiliary subunits of CatSper channels are required for the expression and function. Moreover, all of these auxiliary subunits have huge extracellular domains with minimal cytoplasmic regions, they are as good targets as pore-forming subunits for pharmacological intervention of CatSper channel activity.
Functional Characteristics
Calcium selective ion channel (Ba2+>Ca2+>>Mg2+>>Na+);
quasilinear monovalent cation current in the absence of extracellular divalent cations;
alkalinization shifts the voltage-dependence of activation towards negative potentials [V½ @ pH 6.0 = +87 mV (mouse); V½ @ pH 7.5 = +11mV (mouse) or pH 7.4 = +85 mV (human)]
Ion Selectivity and Conductance
Species:  Human
Rank order:  Ba2+ > Ca2+ > Mg2+ > Na+
References:  11,20
Species:  Mouse
Rank order:  Ba2+ > Ca2+ > Mg2+ > Na+
References:  10
Ion Selectivity and Conductance Comments
Please note that patch clamp is performed on corpus epididymal spermatozoa for mouse but on ejaculate spermatozoa for human.
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  11.0 10.0 10 Epididymal spermatozoa Mouse
Inactivation  - - 10
Comments  pH 7.5
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  87.0 10.0 10 Epididymal spermatozoa Mouse
Inactivation  - - 10
Comments  pH 6
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  85.0 10.0 11 Non-capacitated ejaculate spermatozoa Human
Inactivation  - -
Comments  pH 7.4, 500 pM progesterone shifts V0.5 from +85 to +52 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  70.0 10.0 11 Capacitated ejaculate spermatozoa Human
Inactivation  - -
Comments  pH7.4, capacitation shifts V0.5 from +85 to +70, which is further negatively shifted to + 30 mV by 500 pM progesterone.
Voltage Dependence Comments
pH shifts the half-activation from 87mV at pH6.0 to 11mV at ph 7.5, a dramatic change of -76mV. However, the Boltmann relation is not steep, indicating weak voltage sensitivity. The slope factor (k)=30, which is much less sensitive than channels with positively charged S4 domains such as Kv channels (k=4).

This study was performed in the native ICatSper channel.
Activators
CatSper1 is constitutively active, weakly facilitated by membrane depolarisation, strongly augmented by intracellular alkalinisation. In human, but not mouse, spermatozoa progesterone (EC50 ~ 8 nM) also potentiates the CatSper current (ICatSper).
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
progesterone Hs Full agonist 8.0 – 8.11 pEC50 - -60.0 11,20
pEC50 8.0 – 8.11 (EC50 1x10-8 – 7.7x10-9 M) [11,20]
Holding voltage: -60.0 mV
Description: Patch clamp electrophysiology, kinetic rapid mixing fluometry, 2-3 µM shows the saturating efficacy.
PGE1 Hs Full agonist 6.3 pEC50 - -80.0 11
pEC50 6.3 (EC50 5x10-7 M) [11]
Holding voltage: -80.0 mV
Description: Patch clamp electrophysiology
PGF Hs Full agonist 6.3 pEC50 - -80.0 11
pEC50 6.3 (EC50 5x10-7 M) [11]
Holding voltage: -80.0 mV
Description: Patch clamp electrophysiology
PGE2 Hs Full agonist 6.3 pEC50 - -80.0 11
pEC50 6.3 (EC50 5x10-7 M) [11]
Holding voltage: -80.0 mV
Description: Patch clamp electrophysiology
Activator Comments
Progesterone and prostaglandin activated human ICatSper only.

Mouse CatSper: pH shifts V0.5 from +87 mV at pH6.0 to +11 mV at pH7.5, a dramatic change of -76 mV. However, the Boltmann relation is not steep, indicating weak voltage sensitivity: Slope factor (k)= 30, much less sensitive than channels with positively charged S4 domains (k)=4 for KV channels.
ZP glycoprotein (solubulized ZP; 2 ZP/ul) acts as a non-selective activator of CatSper channels in the principal piece of the sperm tail [22].

Human CatSper: Even at pH7.4, V0.5 is +85 mV, which capacitation shifts to +70 at pH7.4, a slight negative change (-15 mV). Progesterone shifts V0.5 from +85 to +52 (-33 mV), and from +70 to +30 (-40 mV) at pH7.4, in non-capacitated and capacitated human spermatozoa, respectively. Boltmann relation of human CatSper is also not steep: Slope factor (k)=20. A more positive V0.5 and a steeper Slope factor of human CatSper result in a smaller fraction of channels activated at negative membrane potentials compared with mouse CatSper. Therefore, progesterone helps human CatSper achieve a degree of activation at physiological potentials by inducing a negative shift in the G/V curve. The relative effects of activators of human CatSper is progesterone>PGF1a=PGE1>PGA1>PGE2.

In both mouse and human, proton (H+) is an endogenous agonist. Alkalinisation activates ICatSper. For example, mouse ICatSper increases 6-fold (from 2 pA to 12 pA) when pipette pH (pHpip) changes from pH6.0 to pH7.5, which can be further enhanced by 2-fold (22 pA) when pHpip is 8.0.

pEC50 of PGE1, PGF, PGE2 is converted from effective concentration used in the original study.
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
NNC55-0396 Hs Inhibition 5.7 pIC50 - -80.0 – 80.0 11,20
pIC50 5.7 (IC50 2x10-6 M) [11,20]
Holding voltage: -80.0 – 80.0 mV
Description: Patch clamp electrophysiology, kinetic rapid mixing fluometry
NNC55-0396 Mm Inhibition <5.6 pIC50 - -80.0 – 80.0 11
pIC50 <5.6 (IC50 >2.5x10-6 M) [11]
Holding voltage: -80.0 – 80.0 mV
Description: Patch clamp electrophysiology
ruthenium red Mm Inhibition 5.0 pIC50 - - 10
pIC50 5.0 (IC50 1x10-5 M) [10]
Description: Whole cell patch clamp
HC-056456 Hs - 4.7 pIC50 - - 3
pIC50 4.7 (IC50 2x10-5 M) [3]
mibefradil Hs Inhibition 4.4 – 4.52 pIC50 - - 20
pIC50 4.4 – 4.52 (IC50 4x10-5 – 3x10-5 M) [20]
Description: Patch clamp electrophysiology, kinetic rapid mixing fluometry
Cd2+ Mm Inhibition 3.7 pIC50 - - 10
pIC50 3.7 (IC50 2x10-4 M) [10]
Description: Whole cell patch clamp
Ni2+ Mm Inhibition 3.52 pIC50 - - 10
pIC50 3.52 (IC50 3x10-4 M) [10]
Description: Whole cell patch clamp
View species-specific channel blocker tables
Channel Blocker Comments
Blocking calcium (when 2mM extracellular) current through mouse CatSper channels by cadmium, nickel, and ruthenium red are all reversible. Inhibition of mouse ICatSper is not as effective as human ICatSper by 2µM NNC 55-0396.

pIC50 of cadmium, nickel, ruthenium red, NNC 55-0396 and mibefradil is converted from inhibitory concentration used in the original study.
Tissue Distribution
Testis and spermatozoa (plasma membrane of the tail).
Species:  Human
Technique:  RT-PCR, dot-blot, Western blot, patch clamp.
References:  11,13,18
Testis: Expression starts three weeks after birth.
Species:  Mouse
Technique:  RT-PCR
References:  13
Spermatozoa (plasma membrane of the flagellar principal piece).
Species:  Mouse
Technique:  Immunogold EM, patch clamp of isolated whole tail, compared to isolated head and midpiece.
References:  10,18
Testis, mature spermatozoa and falgellar principal piece.
Species:  Mouse
Technique:  Northern blot, Western blot, immunocytochemistry, in situ hybridisation
References:  14,18
Tissue Distribution Comments
To date expression has been comfirmed only in the testis, specifically post-meiotic germ cells and the principal piece of the sperm flagella. Patch clamp electrohysiological measurements are of isolated tail, compared to whole sperm.
Functional Assays
Sperm motility.
Species:  Mouse
Tissue:  Caudal epididymal (mature) spermatozoa.
Response measured:  Path velocity, linear velocity and track velocity measured by Computer Assisted Sperm Analyzer (CASA) over 90 min, hyperactivated motiity (induced by BSA/Bicarbonate incubation; asymmetry by aligned flagellar waveform).
References:  5,14-15,18
In vitro fertilization (IVF).
Species:  Mouse
Tissue:  ZP-intact vs. ZP-free eggs with in vitro capacitated spermatozoa.
Response measured:  The number of fertilized eggs (2-cell embryos) after IVF: none with ZP-intact eggs.
References:  18
Patch clamp electrophysiology.
Species:  Human
Tissue:  Ejaculate spermatozoa (non-capacitated and capacitated).
Response measured:  Current.
References:  11
Patch clamp electrophysiology.
Species:  Mouse
Tissue:  Corpus epididymal spermatozoa.
Response measured:  Current.
References:  10
Fertility.
Species:  Mouse
Tissue: 
Response measured:  The number of matings resulting in pregnancy (none)- male specific infertility.
References:  18
Ca2+ imaging with Fluo-4 in the stopped flow moded fluorescent reader.
Species:  Human
Tissue:  Ejaculate spermatozoa.
Response measured:  Changes in fluorescence.
References:  20
Functional Assay Comments
ICatSper is confined to the principal piece of the sperm tail and activated by alkalinization. Human ICatSper is further activated by progesterone and prostaglandine (PGE1, PGF).
Physiological Functions
Male fertiliy and sperm hyperactivated motility requires CatSper, a Ca2+-selective channel encoded by at least 7 genes encoding distinct subunits of the heteromeric channel complex in mammals (pore-forming CatSpers1-4, and the auxiliary CatSperBeta, Gamma, and Delta). Male mice lacking genes for any of CatSper1-4, or CatSperDelta are infertile.
Species:  Mouse
Tissue:  Epididymal spermatozoa.
References:  4-6,9-10,14-15,18-19
CatSper1-null and CatSper2-null mutant spermatoaz fail to ascend beyond the oviductal reservoir.
Species:  Mouse
Tissue:  Spermatozoa in the female reproductive tract after mating.
References:  7
CatSper channel is essential for normal fertility.
Species:  Human
Tissue:  Ejaculate spermatozoa.
References:  1-2,11,20
Physiological Functions Comments
Sperm cells are slightly acidic internally (pH 6.8) in the vagina (~ pH 5) thus the pH dependence of ICatSper activation leaves it inactive at resting membrane potential. As the pH shifts to ~8 in the cervix and upper female reproductive tract the internal sperm cell pH also becomes alkaline (> pH 7.5) and ICatSper is activated, leading to hyperactivation of motility.
Physiological Consequences of Altering Gene Expression
Infertility as a consequence of loss of hyperactivation of motility. Tageted disruption of CatSper1 gene results in male-specific infertility, decreased sperm motiltiy and loss of cAMP-induced Ca2+ influx.
Species:  Mouse
Tissue:  Testis, spermatozoa
Technique:  Disruption of CatSper1 by deletion of exon 2.
References:  18
Expressing CatSper1-HA-GFP in transgenic mice with a CatSper1-/- background functionally replaces the native CatSper1; ICatSper and cGMP-induced Ca2+ influx in sperm are restored, thus restoring male fertility in the transgenic mice.
Species:  Mouse
Tissue:  Testis, spermatozoa
Technique:  Transgene expression - insertion of HA-eGFP mini-gene in-frame with CatSper1 ORF in a genomic DNA fragment from a BAC clone containing the mouse CatSper1 gene spanning from ~ 4kb 5' to the whole ORF (9kb) to 0.5 kb 3' to the the ORF.
References:  12
Physiological Consequences of Altering Gene Expression Comments
CatSper channel is a heteromeric complex composed of at least 7 proteins, the pore-forming alpha subunits CatSper1-4, and the auxiliary subunits CatSperBeta, CatSperGamma, and CatSperDelta. Their expressions in mature spermatozoa are co-dependent; CatSper1 is undetectable in spermatozoa of CatSper2, 3, 4, and Delta knockout spermatozoa and vice versa, suggesting that all CatSper subunits are required for proper channel assembly.
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ * C57BL/6J
MGI:2179947  MP:0004231 abnormal calcium ion homeostasis PMID: 11595941 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ
MGI:2179947  MP:0002674 abnormal sperm motility PMID: 17227845 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ
MGI:2179947  MP:0004543 abnormal sperm physiology PMID: 17227845 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ * C57BL/6J
MGI:2179947  MP:0002675 asthenozoospermia PMID: 11595941 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ
MGI:2179947  MP:0002675 asthenozoospermia PMID: 17227845 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ * C57BL/6J
MGI:2179947  MP:0004542 impaired acrosome reaction PMID: 11595941 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ * C57BL/6J
MGI:2179947  MP:0000242 impaired fertilization PMID: 11595941 
Catsper1tm1Clph Catsper1tm1Clph/Catsper1tm1Clph
involves: 129X1/SvJ * C57BL/6J
MGI:2179947  MP:0001925 male infertility PMID: 11595941 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Spermatogenic failure 7
OMIM:  612997
Orphanet:  276234
Role: 
Comments: 
References:  1
Click column headers to sort
Type Species Molecular location Description Reference
Insertion: null mutation Human 5-bp insertion after 948 in exon 1 of CatSper1 gene (c.948-949insATGGC) 1
Insertion: null mutation Human 1-bp thymidine insertion at 539 in exon 1 of CatSper1 gene (c.539-540insT) 1

REFERENCES

1. Avenarius MR, Hildebrand MS, Zhang Y, Meyer NC, Smith LL, Kahrizi K, Najmabadi H, Smith RJ. (2009) Human male infertility caused by mutations in the CATSPER1 channel protein. Am. J. Hum. Genet.84 (4): 505-10. [PMID:19344877]

2. Avidan N, Tamary H, Dgany O, Cattan D, Pariente A, Thulliez M, Borot N, Moati L, Barthelme A, Shalmon L, Krasnov T, Ben-Asher E, Olender T, Khen M, Yaniv I, Zaizov R, Shalev H, Delaunay J, Fellous M, Lancet D, Beckmann JS. (2003) CATSPER2, a human autosomal nonsyndromic male infertility gene. Eur. J. Hum. Genet.11 (7): 497-502. [PMID:12825070]

3. Carlson AE, Burnett LA, del Camino D, Quill TA, Hille B, Chong JA, Moran MM, Babcock DF. (2009) Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation. PLoS ONE4 (8): e6844. [PMID:19718436]

4. Carlson AE, Quill TA, Westenbroek RE, Schuh SM, Hille B, Babcock DF. (2005) Identical phenotypes of CatSper1 and CatSper2 null sperm. J. Biol. Chem.280 (37): 32238-44. [PMID:16036917]

5. Carlson AE, Westenbroek RE, Quill T, Ren D, Clapham DE, Hille B, Garbers DL, Babcock DF. (2003) CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm. Proc. Natl. Acad. Sci. U.S.A.100 (25): 14864-8. [PMID:14657352]

6. Chung JJ, Navarro B, Krapivinsky G, Krapivinsky L, Clapham DE. (2011) A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa. Nat Commun2: 153. [PMID:21224844]

7. Ho K, Wolff CA, Suarez SS. (2009) CatSper-null mutant spermatozoa are unable to ascend beyond the oviductal reservoir. Reprod. Fertil. Dev.21 (2): 345-50. [PMID:19210926]

8. Jin J, Jin N, Zheng H, Ro S, Tafolla D, Sanders KM, Yan W. (2007) Catsper3 and Catsper4 are essential for sperm hyperactivated motility and male fertility in the mouse. Biol. Reprod.77 (1): 37-44. [PMID:17344468]

9. Jin JL, O'Doherty AM, Wang S, Zheng H, Sanders KM, Yan W. (2005) Catsper3 and catsper4 encode two cation channel-like proteins exclusively expressed in the testis. Biol. Reprod.73 (6): 1235-42. [PMID:16107607]

10. Kirichok Y, Navarro B, Clapham DE. (2006) Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel. Nature439 (7077): 737-40. [PMID:16467839]

11. Lishko PV, Botchkina IL, Kirichok Y. (2011) Progesterone activates the principal Ca2+ channel of human sperm. Nature471 (7338): 387-91. [PMID:21412339]

12. Liu J, Xia J, Cho KH, Clapham DE, Ren D. (2007) CatSperbeta, a novel transmembrane protein in the CatSper channel complex. J. Biol. Chem.282 (26): 18945-52. [PMID:17478420]

13. Nikpoor P, Mowla SJ, Movahedin M, Ziaee SA, Tiraihi T. (2004) CatSper gene expression in postnatal development of mouse testis and in subfertile men with deficient sperm motility. Hum. Reprod.19 (1): 124-8. [PMID:14688170]

14. Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, Kirichok Y, Ramsey IS, Quill TA, Clapham DE. (2007) All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proc. Natl. Acad. Sci. U.S.A.104 (4): 1219-23. [PMID:17227845]

15. Quill TA, Ren D, Clapham DE, Garbers DL. (2001) A voltage-gated ion channel expressed specifically in spermatozoa. Proc. Natl. Acad. Sci. U.S.A.98 (22): 12527-31. [PMID:11675491]

16. Quill TA, Sugden SA, Rossi KL, Doolittle LK, Hammer RE, Garbers DL. (2003) Hyperactivated sperm motility driven by CatSper2 is required for fertilization. Proc. Natl. Acad. Sci. U.S.A.100 (25): 14869-74. [PMID:14657366]

17. Reardon AJ, Le Goff M, Briggs MD, McLeod D, Sheehan JK, Thornton DJ, Bishop PN. (2000) Identification in vitreous and molecular cloning of opticin, a novel member of the family of leucine-rich repeat proteins of the extracellular matrix. J. Biol. Chem.275 (3): 2123-9. [PMID:10636917]

18. Ren D, Navarro B, Perez G, Jackson AC, Hsu S, Shi Q, Tilly JL, Clapham DE. (2001) A sperm ion channel required for sperm motility and male fertility. Nature413 (6856): 603-9. [PMID:11595941]

19. Roychoudhury C, Jacobs BS, Baker PL, Schultz D, Mehta RH, Levine SR. (2004) Acute ischemic stroke in hospitalized medicare patients: evaluation and treatment. Stroke35 (1): e22-3. [PMID:14657452]

20. Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB. (2011) The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature471 (7338): 382-6. [PMID:21412338]

21. Wang H, Liu J, Cho KH, Ren D. (2009) A novel, single, transmembrane protein CATSPERG is associated with CATSPER1 channel protein. Biol. Reprod.81 (3): 539-44. [PMID:19516020]

22. Xia J, Ren D. (2009) Egg coat proteins activate calcium entry into mouse sperm via CATSPER channels. Biol. Reprod.80 (6): 1092-8. [PMID:19211808]

To cite this database page, please use the following:

Jean-Ju Chung, David E. Clapham.
CatSper and Two-Pore channels: CatSper1. Last modified on 17/03/2014. Accessed on 31/08/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=388.

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