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CatSper4

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Target not currently curated in GtoImmuPdb

Target id: 391

Nomenclature: CatSper4

Family: CatSper and Two-Pore channels (TPC)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 472 1p36.11 CATSPER4 cation channel sperm associated 4 11,15
Mouse 6 1 442 4 D3 Catsper4 cation channel, sperm associated 4 6,12,15
Rat - 1 448 5q36 Catsper4 cation channel, sperm associated 4
Previous and Unofficial Names Click here for help
CatSper3 | cation channel, sperm associated 4 | cation channel
Database Links Click here for help
Alphafold Q7RTX7 (Hs), Q8BVN3 (Mm)
Ensembl Gene ENSG00000188782 (Hs), ENSMUSG00000048003 (Mm), ENSRNOG00000016312 (Rn)
Entrez Gene 378807 (Hs), 329954 (Mm), 362623 (Rn)
Human Protein Atlas ENSG00000188782 (Hs)
KEGG Gene hsa:378807 (Hs), mmu:329954 (Mm), rno:362623 (Rn)
OMIM 609121 (Hs)
Pharos Q7RTX7 (Hs)
RefSeq Nucleotide NM_198137 (Hs), NM_177866 (Mm), NM_001130030 (Mm)
RefSeq Protein NP_937770 (Hs), NP_808534 (Mm), NP_001123502 (Mm)
UniProtKB Q7RTX7 (Hs), Q8BVN3 (Mm)
Wikipedia CATSPER4 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
CatSper1 3,5,8,14-15
CatSper2 3,12-14
CatSper3 5-6,12
Auxiliary Subunits
Name References
CatSperGamma 5,17
CatSperDelta 5
CatSperBeta 5,10
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 Click here for help
Required for ICatSper and male fertility (mouse)
Ion Selectivity and Conductance Click here for help
Species:  Human
Rank order:  Ba2+ > Ca2+ > Mg2+ > Na+
References:  9,16
Species:  Mouse
Rank order:  Ba2+ > Ca2+ > Mg2+ > Na+
References:  8
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 Click here for help
  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  70.0 10.0 9 Capacitated ejaculate spermatozoa Human
Inactivation  - -
Comments  At pH 7.4, capacitation shifts V0.5 from +85 to +70, which is further negatively shifted to + 30 mV by 500 pM progesterone.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  85.0 10.0 9 Non-capacitated ejaculate spermatozoa Human
Inactivation  - -
Comments  At pH 7.4, 500 pM progesterone shifts V0.5 from +85 to +52 mV.

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Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
progesterone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 8.1 pEC50 - -60.0 9,16
⤷ pEC50 8.1 (EC50 7.7x10-9 M) [9,16]
Holding voltage: -60.0 mV
Description: Patch clamp electrophysiology, kinetic rapid mixing fluorometry, 2-3µM shows the saturating efficacy.
PGE1 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure 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 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand 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.
PGF1α Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species 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 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, PGF1α, 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 Value Parameter Concentration range (M) Holding voltage (mV) Reference
NNC55-0396 Small molecule or natural product Click here for species-specific activity table 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 Small molecule or natural product Click here for species-specific activity table 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 Click here for species-specific activity table Mm Antagonist 5.0 pIC50 - - 8
⤷ pIC50 5.0 (IC50 1x10-5 M) [8]
Description: Whole cell patch clamp electrophysiology.
mibefradil Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 4.4 – 4.5 pIC50 - - 16
⤷ pIC50 4.4 – 4.5 (IC50 4x10-5 – 3x10-5 M) [16]
Description: Patch clamp electrophysiology, kinetic rapid mixing fluometry.
Cd2+ Click here for species-specific activity table Mm Antagonist 3.7 pIC50 - - 8
⤷ pIC50 3.7 (IC50 2x10-4 M) [8]
Description: Whole cell patch clamp electrophysiology.
Ni2+ Click here for species-specific activity table Mm Antagonist 3.5 pIC50 - - 8
⤷ pIC50 3.5 (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 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 Click here for help
Testis
Species:  Human
Technique:  RT-PCR
References:  11
Testis: expression restricted to germ cells, especially noted in the principal piece of the spermatozoal flagella.
Species:  Mouse
Technique:  In situ hybridisation, northern blot, RT-PCR, Western blot, immunocytochemistry, patch clamp electrophysiology.
References:  5-7,12
Tissue Distribution Comments
Expression has only been reported in testis to date, specifically meiotic and post-meiotic germ cells and the principal piece of the sperm flagella.
Functional Assays Click here for help
Patch clamp electrophysiology.
Species:  Mouse
Tissue:  Corpus epididymal spermatozoa.
Response measured:  Current
References:  12
Patch clamp electrophysiology.
Species:  Human
Tissue:  Ejaculate spermatozoa (non-capacitated and capacitated).
Response measured:  Current
References:  9
Sperm motility
Species:  Mouse
Tissue:  Caudal epididymal spermatozoa
Response measured:  Average forward velocity such as linear velocity, track velocity, and percent motile is significantly decreased in CatSper4 knockout spermatozoa compared with wildtype. No hyperactivated motility for CatSper3 null sperm probed by flagellar asymmetry.
References:  6,12
Fertility
Species:  Mouse
Tissue:  In vivo.
Response measured:  No litters produced when CatSper3−/− and CatSper4−/− male mice are mated with wildtype females i.e. male specific infertility resulting from CatSper 3 or 4 gene knockout.
References:  6,12
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, PGF1&alpha;). CatSper1, 2, and 3 knockout mice show identical phenotype.
Physiological Functions Click here for help
CatSper 1-4 together form a channel that is required for mouse sperm hyperactivation of motility, and consequently fertility.
Species:  Mouse
Tissue:  Spermatozoa
References:  4,8,12-13,15
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 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:  Epididymal spermatozoa.
References:  3-5,7-8,12-13,15
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 achieve 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 Click here for help
Tageted disruption of CatSper4 gene shows defect in hyperactivated sperm motility required for male fertility in the mouse.
Species:  Mouse
Tissue:  Testis, spermtozoa.
Technique:  Deletion of exon 1 to 3 (PMID:17344468), deletion of exon 4 to 8 (PMID:17227845).
References:  6,12
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; CatSper4 is undetectable in spermatozoa of CatSperDelta knockout spermatozoa and vice versa, suggesting that all CatSper subunits are required for proper channel assembly.
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Catsper4tm1Clph Catsper4tm1Clph/Catsper4tm1Clph
involves: 129S4/SvJae		 MGI:3043288  MP:0002674 abnormal sperm motility PMID: 17227845 
Catsper4tm1Wyan Catsper4tm1Wyan/Catsper4tm1Wyan
involves: 129S7/SvEvBrd * C57BL/6J		 MGI:3043288  MP:0002674 abnormal sperm motility PMID: 17344468 
Catsper4tm1Clph Catsper4tm1Clph/Catsper4tm1Clph
involves: 129S4/SvJae		 MGI:3043288  MP:0004543 abnormal sperm physiology PMID: 17227845 
Catsper4tm1Clph Catsper4tm1Clph/Catsper4tm1Clph
involves: 129S4/SvJae		 MGI:3043288  MP:0002675 asthenozoospermia PMID: 17227845 
Catsper4tm1Clph Catsper4tm1Clph/Catsper4tm1Clph
involves: 129S4/SvJae		 MGI:3043288  MP:0003666 impaired sperm capacitation PMID: 17227845 
Catsper4tm1Clph Catsper4tm1Clph/Catsper4tm1Clph
involves: 129S4/SvJae		 MGI:3043288  MP:0001925 male infertility PMID: 17227845 
Catsper4tm1Wyan Catsper4tm1Wyan/Catsper4tm1Wyan
involves: 129S7/SvEvBrd * C57BL/6J		 MGI:3043288  MP:0001925 male infertility PMID: 17344468 
Catsper4tm1Clph Catsper4tm1Clph/Catsper4tm1Clph
involves: 129S4/SvJae		 MGI:3043288  MP:0005578 teratozoospermia PMID: 17227845 
Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Mouse
Description:  Mus musculus cation channel, sperm associated 4, transcript variant 1
Nucleotide accession:  NM_177866
Protein accession:  NP_808534
References:  12
Type:  Splice variant
Species:  Mouse
Description:  Mus musculus cation channel, sperm associated 4, transcript variant 2
Nucleotide accession:  NM_001130030
Protein accession:  NP_001123502
References:  7

References

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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 et al.. (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 USA, 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 Commun, 2: 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. Nature, 439 (7077): 737-40. [PMID:16467839]

9. Lishko PV, Botchkina IL, Kirichok Y. (2011) Progesterone activates the principal Ca2+ channel of human sperm. Nature, 471 (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 USA, 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 USA, 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 USA, 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. Nature, 413 (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. Nature, 471 (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]

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