More information on this family may be found on the IUPHAR-DB family and introduction pages.
CatSper channels (CatSper1-4; nomenclature as agreed by NC-IUPHAR, [4]) are putative 6TM, voltage-gated, calcium permeant channels that are presumed to assemble as a tetramer of α-like subunits and mediate the current ICatSper. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Cav) [16]. CatSper1 [16], CatSper2 [15] and CatSpers 3 and 4 [6,11,14], in common with a recently identified putative 2TM auxiliary CatSperβ protein [10] and two putative 1TM associated CatSperγ and CatSperδ proteins [3,18], are restricted to the testis and localised to the principle piece of sperm tail.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Clapham, DE; Garbers, DL. (2005) International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels. Pharmacol. Rev., 57 (4): 451-4. [PMID:16382101]
Hildebrand, MS; Avenarius, MR; Fellous, M; Zhang, Y; Meyer, NC; Auer, J; Serres, C; Kahrizi, K; Najmabadi, H; Beckmann, JS; et al.. (2010) Genetic male infertility and mutation of CATSPER ion channels. Eur. J. Hum. Genet., 18 (11): 1178-84. [PMID:20648059]
Kirichok, Y; Lishko, PV. (2011) Rediscovering sperm ion channels with the patch-clamp technique. Mol. Hum. Reprod., 17 (8): 478-99. [PMID:21642646]
Lishko, PV; Kirichok, Y. (2010) The role of Hv1 and CatSper channels in sperm activation. J. Physiol. (Lond.), 588 (Pt 23): 4667-72. [PMID:20679352]
Navarro, B; Kirichok, Y; Chung, JJ; Clapham, DE. (2008) Ion channels that control fertility in mammalian spermatozoa. Int. J. Dev. Biol., 52 (5-6): 607-13. [PMID:18649274]
Publicover, SJ; Giojalas, LC; Teves, ME; de Oliveira, GS; Garcia, AA; Barratt, CL; Harper, CV. (2008) Ca2+ signalling in the control of motility and guidance in mammalian sperm. Front. Biosci., 13: 5623-37. [PMID:18508611]
Quill, TA; Wang, D; Garbers, DL. (2006) Insights into sperm cell motility signaling through sNHE and the CatSpers. Mol. Cell. Endocrinol., 250 (1-2): 84-92. [PMID:16413670]
Ren, D; Xia, J. (2010) Calcium signaling through CatSper channels in mammalian fertilization. Physiology (Bethesda), 25 (3): 165-75. [PMID:20551230]
Suarez, SS. (2008) Control of hyperactivation in sperm. Hum. Reprod. Update, 14 (6): 647-57. [PMID:18653675]
Zhang, D; Gopalakrishnan, M. (2005) Sperm ion channels: molecular targets for the next generation of contraceptive medicines?. J. Androl., 26 (6): 643-53. [PMID:16293573]
1. 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]
2. 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]
3. 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]
4. Clapham, DE; Garbers, DL. (2005) International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels. Pharmacol. Rev., 57 (4): 451-4. [PMID:16382101]
5. Hildebrand, MS; Avenarius, MR; Fellous, M; Zhang, Y; Meyer, NC; Auer, J; Serres, C; Kahrizi, K; Najmabadi, H; Beckmann, JS; et al.. (2010) Genetic male infertility and mutation of CATSPER ion channels. Eur. J. Hum. Genet., 18 (11): 1178-84. [PMID:20648059]
6. 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]
7. 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]
8. Lishko, PV; Botchkina, IL; Kirichok, Y. (2011) Progesterone activates the principal Ca2+ channel of human sperm. Nature, 471 (7338): 387-91. [PMID:21412339]
9. Lishko, PV; Kirichok, Y. (2010) The role of Hv1 and CatSper channels in sperm activation. J. Physiol. (Lond.), 588 (Pt 23): 4667-72. [PMID:20679352]
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. Martínez-López, P; Santi, CM; Treviño, CL; Ocampo-Gutiérrez, AY; Acevedo, JJ; Alisio, A; Salkoff, LB; Darszon, A. (2009) Mouse sperm K+ currents stimulated by pH and cAMP possibly coded by Slo3 channels. Biochem. Biophys. Res. Commun., 381 (2): 204-9. [PMID:19338774]
13. Navarro, B; Kirichok, Y; Clapham, DE. (2007) KSper, a pH-sensitive K+ current that controls sperm membrane potential. Proc. Natl. Acad. Sci. U.S.A., 104 (18): 7688-92. [PMID:17460039]
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. 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]
17. 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]
18. 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]
19. 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]
20. Zeng, XH; Yang, C; Kim, ST; Lingle, CJ; Xia, XM. (2011) Deletion of the Slo3 gene abolishes alkalization-activated K+ current in mouse spermatozoa. Proc. Natl. Acad. Sci. U.S.A., 108 (14): 5879-84. [PMID:21427226]
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CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems [15-16]. The properties of CatSper1 tabulated above are derived from whole cell voltage-clamp recordings comparing currents endogenous to spermatozoa isolated from the corpus epididymis of wild-type and Catsper1(-/-) mice [7] and also mature human sperm [8,17]. ICatSper is also undetectable in the spermatozoa of Catsper2(-/-),Catsper3(-/-), or Catsper4(-/-) mice and CatSper 1 associates with CatSper 2, 3, or 4 in heterologous expression systems [14]. Moreover, targeted disruption of Catsper1, 2, 3, or 4 genes results in an identical phenotype in which spermatozoa fail to exhibit the hyperactive movement (whip-like flagellar beats) necessary for penetration of the egg cumulus and zona pellucida and subsequent fertilization. Such disruptions are associated with a deficit in alkalinization and depolarization-evoked Ca2+ entry into spermatozoa [1-2,14]. Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1-4 [14] in association with the auxiliary subunits (β, γ, δ) that are also essential for function [3]. CatSper channels are required for the increase in intracellular Ca2+ concentration in sperm evoked by egg zona pellucida glycoproteins [19]. The driving force for Ca2+ entry is principally determined by a mildly outwardly rectifying K+ channel (KSper) that, like CatSpers, is activated by intracellular alkalinization [13]. Mouse KSper is encoded by mSlo3, a protein detected only in testis [12-13,20]. In human sperm, such alkalinization may result from the activation of Hv1, a proton channel [9]. Mutations in CatSpers are associated with syndromic and non-syndromic male infertility [5]. In human ejaculated spermatozoa, progesterone (<50 nM) potentiates the CatSper current by a non-genomic mechanism and acts synergistically with intracellular alkalinisation [8,17]. In addition, certain prostaglandins (e.g. PGF1α, PGE1) also potentiate CatSper mediated currents [8,17].