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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 | 398 | 5q31.1 | CATSPER3 | cation channel sperm associated 3 | 6,11,15 |
| Mouse | 6 | 1 | 395 | 13 B1 | Catsper3 | cation channel, sperm associated 3 | 6,12,15 |
| Rat | 6 | 1 | 301 | 17p14 | Catsper3 | cation channel, sperm associated 3 | |
| Previous and Unofficial Names |
| Cation channel of sperm; 4 | CatSper4 | CACRC | cation channel |
| Database Links |
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| Alphafold | Q86XQ3 (Hs), Q80W99 (Mm) |
| Ensembl Gene | ENSG00000152705 (Hs), ENSMUSG00000021499 (Mm), ENSRNOG00000011374 (Rn) |
| Entrez Gene | 347732 (Hs), 76856 (Mm), 290989 (Rn) |
| Human Protein Atlas | ENSG00000152705 (Hs) |
| KEGG Gene | hsa:347732 (Hs), mmu:76856 (Mm), rno:290989 (Rn) |
| OMIM | 609120 (Hs) |
| Pharos | Q86XQ3 (Hs) |
| RefSeq Nucleotide | NM_178019 (Hs), NM_029772 (Mm), NM_001252488 (Mm), NM_001252487 (Mm), NM_001106101 (Rn) |
| RefSeq Protein | NP_821138 (Hs), NP_001239417 (Mm), NP_001239416 (Mm), NP_084048 (Mm), NP_001099571 (Rn) |
| UniProtKB | Q86XQ3 (Hs), Q80W99 (Mm) |
| Wikipedia | CATSPER3 (Hs) |
| Associated Proteins |
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| 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. |
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| Functional Characteristics |
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| Required for ICatSper and male fertility (mouse) | |
| 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. 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 |
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Download all structure-activity data for this target as a CSV file 
| Activators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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, 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 (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. |
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| Tissue Distribution
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| 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. |
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| 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 prostaglandins (PGE1, PGF1α). CatSper1, 2, and 4 knockout mice show identical phenotype. |
| Physiological Functions
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| 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
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| 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
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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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]
