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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How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.
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.