Nomenclature: CatSper3

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 1 398 5q31.1 CATSPER3 cation channel, sperm associated 3 6,11,15
Mouse 6 1 395 13 B2 Catsper3 cation channel, sperm associated 3 6,12,15
Rat 6 1 301 17p14 Catsper3 cation channel, sperm associated 3
Previous and Unofficial Names
CatSper4
Cation channel of sperm; 4
CACRC
Catsper3_predicted
LOC290989
cation channel sperm-associated protein 3
cation channel, sperm associated 3
cation channel, sperm associated 3 (predicted)
4921522D01Rik
Database Links
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
CatSper2 3,12-14
CatSper1 3,5,8,14-15
CatSper4 5-6,12
Auxiliary Subunits
Name References
CatSperBeta 5,10
CatSperGamma 5,17
CatSperDelta 5
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
CatSper1-4 appear to function only as a heterotetramer, producing a current known as ICatSper. Expression of all CatSper subunits 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
Required for ICatSper
Ion Selectivity and Conductance
Species:  Mouse
Rank order:  Ba2+ > Mg2+ = Ca2+ > Na+
References:  8
Species:  Rat
Rank order:  Ba2+ [4.0 pS] > Ca2+ > Mg2+ > Na+
References:  9,16
Ion Selectivity and Conductance Comments
Please note that patch clamp is performed on corpus epididymal spermatozoa for mouse but on ejaculate spermatozoa for human. Since CatSper1-4 are pore-forming subunits which are all required for ICatSper, the electrophysiological characterization of CatSper channel is common to CatSper1, 2, 3, and 4.
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  11.0 10.0 8 Epididymal spermatozoa Mouse
Inactivation  - - 8
Comments  At pH 7.5
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  87.0 10.0 8 Epididymal spermatozoa Mouse
Inactivation  - - 8
Comments  At pH 6.0
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  85.0 10.0 9 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 9 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.
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 8.11 pEC50 - -60.0 9,16
pEC50 8.11 (EC50 7.7x10-9 M) [9,16]
Holding voltage: -60.0 mV
Description: Patch clamp electrophysiology, kinetic rapid mixing fluometry, 2-3µM shows the saturating efficacy.
PGE1 Hs Full agonist 6.3 pEC50 - -80.0 9
pEC50 6.3 (EC50 5x10-7 M) [9]
Holding voltage: -80.0 mV
Description: Patch clamp electrophysiology.
PGE2 Hs Full agonist 6.3 pEC50 - -80.0 9
pEC50 6.3 (EC50 5x10-7 M) [9]
Holding voltage: -80.0 mV
Description: Patch clamp electrophysiology.
PGF Hs Full agonist 6.3 pEC50 - -80.0 9
pEC50 6.3 (EC50 5x10-7 M) [9]
Holding voltage: -80.0 mV
Description: Patch clamp electrophysiology.
Activator Comments
Progesterone and prostaglandin activate human ICatSper only. Mouse CatSper: pH shifts V0.5 from +87 mV at pH 6.0 to +11 mV at pH 7.5, 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. Human CatSper: Even at pH 7.4, V0.5 is +85 mV, which capacitation shifts to +70 at pH 7.4, 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 factroe (k)=20. A more positive V0.5 and a steeper Slope factor of human CatSper resulting 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 9,16
pIC50 5.7 (IC50 2x10-6 M) [9,16]
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 9
pIC50 <5.6 (IC50 >2.5x10-6 M) [9]
Holding voltage: -80.0 – 80.0 mV
Description: Patch clamp electrophysiology.
ruthenium red Mm Antagonist 5.0 pIC50 - - 8
pIC50 5.0 (IC50 1x10-5 M) [8]
Description: Whole cell patch clamp electrophysiology.
mibefradil Hs Inhibition 4.4 – 4.52 pIC50 - - 16
pIC50 4.4 – 4.52 (IC50 4x10-5 – 3x10-5 M) [16]
Description: Patch clamp electrophysiology, kinetic rapid mixing fluometry.
Cd2+ Mm Antagonist 3.7 pIC50 - - 8
pIC50 3.7 (IC50 2x10-4 M) [8]
Description: Whole cell patch clamp electrophysiology.
Ni2+ Mm Antagonist 3.52 pIC50 - - 8
pIC50 3.52 (IC50 3x10-4 M) [8]
Description: Whole cell patch clamp electrophysiology.
View species-specific channel blocker tables
Channel Blocker Comments
Blocking calcium (2mM) 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 2 uM 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- germ cells only: From P20 onwards, sperm tail, principal piece, plasma membrane of the tail.
Species:  Mouse
Technique:  In situ hybridisation, northern blot, Western blot, immunocytochemistry, patch clamp electrophysiology, RT-PCR.
References:  5-7,12
Tissue Distribution Comments
Expression has been described only in testis the to date, specifically meiotic and post-meiotic germ cells and the principal piece of the sperm flagella.

Patch clamp of CatSper3 knockout spermatozoa, compared with all other CatSper1, 2, and 4 knockout spermazoa shows the absence of ICatSper.
Functional Assays
Patch clamp electrophysiology.
Species:  Mouse
Tissue:  Corpus epididymal spermatozoa.
Response measured:  Current.
References:  6,12
Sperm motility and fertility.
Species:  Mouse
Tissue:  Caudal epididymal spermatozoa.
Response measured:  Average forward velocity such as linear velocity, track velocity, and percent motile is significantly decreased in CatSper3 knock-out spermatozoa compared with wild-type. No hyperactivated motility for CatSper3 null sperm detected when probed by flagellar asymmetry. Resulting on no pregnancies following matings i.e. male-specific infertility.
References:  6,12
Patch clamp electrophysiology.
Species:  Human
Tissue:  Ejaculate spermatozoa (non-capacitated and capacitated).
Response measured:  Current.
References:  9
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 prostaglandins (PGE1, PGF1α). CatSper1, 2, and 4 knockout mice show identical phenotype.
Physiological Functions
CatSper 1-4 together form a channel that is required for mouse sperm hyperactivation of motility, and consequently fertility. 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 any of CatSper1-4, or the Delta gene are infertile. Sperm cells are slightly acidic internally (pH 6.8) in the vagina (e.g. pH 5), and thus ICatSper is inactive at resting membrane potential (-40 mV). As pH shifts to ~8 at the cervix and upper female reproductive tract, internal sperm cell pH also becomes alkaline (pH >7.5). pH shifts half activation from 87 mV at pH 6.0 to 11 mV at pH 7.5, a dramatic change of -76 mV.
Species:  Mouse
Tissue:  Spermatozoa
References:  3-4,7-8,12-13,15
Humans with mutations or deletions in CatSper1 and CatSper2 are infertile. Human ICatSper is activated by alkalinization and further potentiated by progesterone and prostagladins. Half activation (V0.5) of human CatSper is 85 mV, indicating that a very small fraction is active at physiological membrane potential. However, progesterone shifts V0.5 from +85 to +52, and from +70 to +30 in, in non-capacitated and capacitated human spermatozoa, respectively, therefore human CatSper achieves a similar degree of actiation at physiological potentials as mouse CatSper.
Species:  Human
Tissue:  Ejaculate spermatozoa.
References:  1-2,9,16
Physiological Functions Comments
Since CatSper1-4 are pore-forming subunits which are all required for ICatSper, the physiological function of CatSper1, 2, 3, and 4 is identical.
Physiological Consequences of Altering Gene Expression
Infertility as a consequence of loss of hyperactivation of motility.
Species:  Mouse
Tissue:  Spermatozoa
Technique:  Targeted gene disruption
1. Deletion of exons 4 and 5 (PMID: 16107607)
2. Deletion of exons 4 to 7 (PMID: 17227845).
References:  7,12
Physiological Consequences of Altering Gene Expression Comments
CatSper channel is a heteromeric complex composed of at least 7 proteins, pore-forming alpha subunits CatSper1-4, and auxiliary subunits CatSperBeta, CatSperGamma, and CatSperDelta. Their expressions in mature spermatozoa are co-dependent; CatSper2 is undetectable in spermatozoa of CatSper1 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

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Catsper3tm1Clph Catsper3tm1Clph/Catsper3tm1Clph
involves: 129S4/SvJae
MGI:1924106  MP:0002674 abnormal sperm motility PMID: 17227845 
Catsper3tm1Wyan Catsper3tm1Wyan/Catsper3tm1Wyan
involves: 129S7/SvEvBrd * C57BL/6J
MGI:1924106  MP:0002674 abnormal sperm motility PMID: 17344468 
Catsper3tm1Clph Catsper3tm1Clph/Catsper3tm1Clph
involves: 129S4/SvJae
MGI:1924106  MP:0004543 abnormal sperm physiology PMID: 17227845 
Catsper3tm1Clph Catsper3tm1Clph/Catsper3tm1Clph
involves: 129S4/SvJae
MGI:1924106  MP:0002675 asthenozoospermia PMID: 17227845 
Catsper3tm1Clph Catsper3tm1Clph/Catsper3tm1Clph
involves: 129S4/SvJae
MGI:1924106  MP:0003666 impaired sperm capacitation PMID: 17227845 
Catsper3tm1Clph Catsper3tm1Clph/Catsper3tm1Clph
involves: 129S4/SvJae
MGI:1924106  MP:0001925 male infertility PMID: 17227845 
Catsper3tm1Wyan Catsper3tm1Wyan/Catsper3tm1Wyan
involves: 129S7/SvEvBrd * C57BL/6J
MGI:1924106  MP:0001925 male infertility PMID: 17344468 
Catsper3tm1Clph Catsper3tm1Clph/Catsper3tm1Clph
involves: 129S4/SvJae
MGI:1924106  MP:0005578 teratozoospermia PMID: 17227845 
Biologically Significant Variants
Type:  Splice variant.
Species:  Mouse
Description:  Mus musculus cation channel, sperm associated 3, transcript variant 1
Nucleotide accession: 
Protein accession: 
References:  12
Type:  Splice variant.
Species:  Mouse
Description:  Mus musculus cation channel, sperm associated 3, transcript variant 2.
Nucleotide accession: 
Protein accession: 
References:  7
Type:  Splice variant.
Species:  Mouse
Description:  Mus musculus cation channel, sperm associated 3, transcript variant 3.
Nucleotide accession: 
Protein accession: 

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, 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

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

10. 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]

11. Lobley A, Pierron V, Reynolds L, Allen L, Michalovich D. (2003) Identification of human and mouse CatSper3 and CatSper4 genes: characterisation of a common interaction domain and evidence for expression in testis. Reprod. Biol. Endocrinol.1: 53. [PMID:12932298]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

To cite this database page, please use the following:

Jean-Ju Chung, David E. Clapham.
CatSper and Two-Pore channels: CatSper3. Last modified on 14/08/2013. Accessed on 30/08/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=390.

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