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Gene and Protein Information  |
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| Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 6 | 1 | 780 | 11q13.1 | 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 |
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| Cation channel of sperm [18] | cation channel sperm-associated protein 1 [18] | CatSper (mouse) [18] | SPGF7 (human) | cation channel, sperm associated 1 | cation channel | |
| Database Links |
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| Alphafold | Q8NEC5 (Hs), Q91ZR5 (Mm) |
| ChEMBL Target | CHEMBL1628462 (Hs), CHEMBL3886121 (Mm) |
| Ensembl Gene | ENSG00000175294 (Hs), ENSMUSG00000038498 (Mm), ENSRNOG00000056208 (Rn) |
| Entrez Gene | 117144 (Hs), 225865 (Mm), 689349 (Rn) |
| Human Protein Atlas | ENSG00000175294 (Hs) |
| KEGG Gene | hsa:117144 (Hs), mmu:225865 (Mm), rno:689349 (Rn) |
| OMIM | 606389 (Hs) |
| Orphanet | ORPHA279661 (Hs) |
| Pharos | Q8NEC5 (Hs) |
| RefSeq Nucleotide | NM_053054 (Hs), NM_139301 (Mm) |
| RefSeq Protein | NP_444282 (Hs), NP_647462 (Mm) |
| UniProtKB | Q8NEC5 (Hs), Q91ZR5 (Mm) |
| Wikipedia | CATSPER1 (Hs) |
| Associated Proteins |
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| 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. |
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| Functional Characteristics |
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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)]; required for ICatSper and male fertility (mouse and human) |
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| Ion Selectivity and Conductance |
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| 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 |
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| 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. |
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| Activators |
| CatSper1 is constitutively active, weakly facilitated by membrane depolarisation, strongly augmented by intracellular alkalinisation. In human, but not mouse, progesterone (EC50 ~ 8 nM) also potentiates the CatSper current (ICatSper). [11,20] |
Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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, PGF1α, PGE2 is converted from effective concentration used in the original study. |
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| Channel Blockers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. |
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| Tissue Distribution
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| 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
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| 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, PGF1α). |
| Physiological Functions
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| 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
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| 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
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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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, 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 ONE, 4 (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 USA, 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 Commun, 2: 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. Nature, 439 (7077): 737-40. [PMID:16467839]
11. Lishko PV, Botchkina IL, Kirichok Y. (2011) Progesterone activates the principal Ca2+ channel of human sperm. Nature, 471 (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 USA, 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 USA, 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 USA, 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. Nature, 413 (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. Stroke, 35 (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. Nature, 471 (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]
