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CatSper and Two-Pore channels (TPC) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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CatSper channels (CatSper1-4, nomenclature as agreed by NC-IUPHAR [10]) are putative 6TM, voltage-gated, alkalinization-activated calcium permeant channels that are presumed to assemble as a tetramer of α-like subunits and mediate the current ICatSper [16]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Cav) [27]. CatSper1 [27], CatSper2 [26] and CatSpers 3 and 4 [15,20,25], in common with a putative 2TM auxiliary CatSperβ protein [19] and two putative 1TM associated CatSperγ and CatSperδ proteins [8,32], are restricted to the testis and localised to the principle piece of sperm tail. The novel cross-species CatSper channel inhibitor, RU1968, has been proposed as a useful tool to aid characterisation of native CatSper channels [28].
Two-pore channels (TPCs) are structurally related to CatSpers, CaVs and NaVs. TPCs have a 2x6TM structure with twice the number of TMs of CatSpers and half that of CaVs. There are three animal TPCs (TPC1-TPC3). Humans have TPC1 and TPC2, but not TPC3. TPC1 and TPC2 are localized in endosomes and lysosomes [2]. TPC3 is also found on the plasma membrane and forms a voltage-activated, non-inactivating Na+ channel [3]. All the three TPCs are Na+-selective under whole-cell or whole-organelle patch clamp recording [4-5,34]. The channels may also conduct Ca2+ [23].
Channels and Subunits
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CatSper1
C
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CatSper2
C
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CatSper3
C
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CatSper4
C
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TPC1
C
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TPC2
C
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Further reading
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Striessnig J, Gibb AJ, Mathie AA, Veale EL, Kelly E, Peach CJ, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Ion channels. Br J Pharmacol. 182: S152-S241.
CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems [26-27]. 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 [16] and also mature human sperm [17,31]. ICatSper is also undetectable in the spermatozoa of Catsper2(-/-), Catsper3(-/-), Catsper4(-/-), or CatSperδ (-/-) mice, and CatSper 1 associates with CatSper 2, 3, 4, β, γ, and δ [8,19,25]. Moreover, targeted disruption of Catsper1, 2, 3, 4, or δ 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 [7-8,25]. Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1-4 [25] in association with the auxiliary subunits (β, γ, δ) that are also essential for function [8]. CatSper channels are required for the increase in intracellular Ca2+ concentration in sperm evoked by egg zona pellucida glycoproteins [34]. Mouse and human sperm swim against the fluid flow and Ca2+ signaling through CatSper is required for the rheotaxis [22]. In vivo, CatSper1-null spermatozoa cannot ascend the female reproductive tracts efficiently [9,14]. It has been shown that CatSper channels form four linear Ca2+ signaling domains along the flagella, which orchestrate capacitation-associated tyrosine phosphorylation [9].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 [24]. Mouse KSper is encoded by mSlo3, a protein detected only in testis [21,24,35]. In human sperm, such alkalinization may result from the activation of Hv1, a proton channel [18]. Mutations in CatSpers are associated with syndromic and non-syndromic male infertility [13]. In human ejaculated spermatozoa, progesterone (<50 nM) potentiates the CatSper current by a non-genomic mechanism and acts synergistically with intracellular alkalinisation [17,31]. Sperm cells from infertile patients with a deletion in CatSper2 gene lack ICatSper and the progesterone response [30]. In addition, certain prostaglandins (e.g. PGF1α, PGE1) also potentiate CatSper mediated currents [17,31].
In human sperm, CatSper channels are also activated by various small molecules including endocrine disrupting chemicals and proposed as a polymodal sensor [1,1].
TPCs are the major Na+ conductance in lysosomes; knocking out TPC1 and TPC2 eliminates the Na+ conductance and renders the organelle’s membrane potential insensitive to changes in [Na+] (31). The channels are regulated by luminal pH [4], PI(3,5)P2 [33], intracellular ATP and extracellular amino acids [5]. TPCs are also involved in the NAADP-activated Ca2+ release from lysosomal Ca2+ stores [2,23]. Mice lacking TPCs are viable but have phenotypes including compromised lysosomal pH stability, reduced physical endurance [5], resistance to Ebola viral infection [29] and fatty liver [12]. No major human disease-associated TPC mutation has been reported.