CatSper channels

Overview: CatSper channels (CatSpers1–4; nomenclature as agreed by NC-IUPHAR, Clapham and Garbers, 2005) are putative 6TM, voltage-gated, calcium-permeant channels that are presumed to assemble as a tetramer of α-like subunits and mediate the current I_CatSper. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Ca_v) (Ren et al., 2001). CatSper1 (Ren et al., 2001), CatSper2 (Quill et al., 2001) and CatSpers3 and 4 (Lobley et al., 2003; Lin et al., 2005; Qi et al., 2007), in common with a recently identified putative 2TM-auxiliary CatSperβ protein (Liu et al., 2007) and a putative 1TM-associated CatSperγ protein (Wang et al., 2009), are restricted to the testis and localized to the principle piece of sperm tail.

Nomenclature	CatSper1	CatSper2	CatSper3	CatSper4
Ensembl ID	ENSG00000175294	ENSG00000166762	ENSG00000152705	ENSG00000188782
Activators	Constitutively active, weakly facilitated by membrane depolarization, strongly augmented by intracellular alkalinization	–	–	–
Blockers	Cd2+ (200 μM), Ni2+ (300 μM), ruthenium red (10 μM)	–	–	–
Functional characteristics	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 at pH 6.0 =+87 mV; V½ at pH 7.5 =+11 mV)	Required for ICatSper	Required for ICatSper	Required for ICatSper

CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems (Quill et al., 2001; Ren et al., 2001). The properties of CatSper1 tabulated above are derived from whole cell voltage-clamp recordings comparing currents endogenous with spermatozoa isolated from the corpus epididymis of wild-type and Catsper1^(−/−) mice (Kirichok et al., 2006). I_CatSper is also undetectable in the spermatozoa of Catsper2^(−/−), Catsper3^(−/−) or Catsper4^(−/−) mice, and CatSper 1 associates with CatSpers2, 3 or 4 in heterologous expression systems (Qi et al., 2007). Moreover, targeted disruption of Catspers1, 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 (Carlson et al., 2003; 2005; Qi et al., 2007). Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1–4 (Qi et al., 2007). CatSper channels are required for the increase in intracellular Ca²⁺ concentration in sperm evoked by egg zona pellucida glycoproteins (Xia and Ren, 2009). 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 (Navarro et al., 2007). KSper is not yet identified, but its properties are most consistent with mSlo3, a protein detected only in testis (Navarro et al., 2007).

Further Reading

Clapham DE, Garbers DL (2005). International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels. Pharmacol Rev57: 451–454.

Navarro B, Kirichok Y, Chung JJ, Clapham DE (2008). Ion channels that control fertility in mammalian spermatozoa. Int J Dev Biol52: 607–613.

Publicover SJ, Giojalas LC, Teves ME, de Oliveira GS, Garcia AA, Barratt CL et al. (2008). Ca²⁺ signalling in the control of motility and guidance in mammalian sperm. Front Biosci13: 5623–5637.

Quill TA, Wang D, Garbers DL (2006). Insights into sperm cell motility through sNHE and the CatSpers. Mol Cell Endocrinol250: 84–92.

Suarez SS (2008). Control of hyperactivation in sperm. Hum Reprod Update 14: 647–657.

Zhang D, Gopalakrishnan M (2005). Sperm ion channels: molecular targets for the next generation of contraceptive medicines? J Androl26: 643–653.