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Activation of CatSper by extracellular cAMP and kinetics of the 8-CPT-cAMP-evoked Ca 2+ response in human sperm. (A) Representative Ca 2+ signals evoked by cAMP in sperm from a healthy donor (upper panel), and averaged Ca 2+ signal (lower panel, n = 3) in sperm lacking functional CatSper channels (CATSPER2 -/-). The buffer control was subtracted (B) Mean maximal amplitudes of Ca 2+ signals evoked by cAMP (n = 4) and the vehicle (NaCl) (n = 3) after subtraction of the buffer control. (C) Ca 2+ signal evoked by rapid mixing of sperm with 8-CPT-cAMP (5 mM) in a stopped-flow apparatus. (D) Onset of the 8-CPT-cAMP-evoked Ca 2+ signal from (C) shown on an extended time scale.
Source publication
The sperm-specific CatSper channel controls the influx of Ca2+ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activ...
Contexts in source publication
Context 1
... whether CatSper might also be activated by extracellular application of cAMP itself, which hardly permeates the cell membrane. Indeed, not only its membranepermeable analogs, but also cAMP (at ≥ 1 mM), evoked a [Ca 2+ ] i increase in human sperm (Fig. 4A, B). The cAMP-evoked Ca 2+ response was abolished in sperm that lack functional CatSper (Fig. 4A). Next, we examined the kinetics of the Ca 2+ signals evoked by 8-CPT-cAMP in a stopped-flow apparatus. Upon rapid mixing of sperm with 8-CPT-cAMP, [Ca 2+ ] i rose with no measurable latency within the time resolution of the system (36 ms) ...
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... whether CatSper might also be activated by extracellular application of cAMP itself, which hardly permeates the cell membrane. Indeed, not only its membranepermeable analogs, but also cAMP (at ≥ 1 mM), evoked a [Ca 2+ ] i increase in human sperm (Fig. 4A, B). The cAMP-evoked Ca 2+ response was abolished in sperm that lack functional CatSper (Fig. 4A). Next, we examined the kinetics of the Ca 2+ signals evoked by 8-CPT-cAMP in a stopped-flow apparatus. Upon rapid mixing of sperm with 8-CPT-cAMP, [Ca 2+ ] i rose with no measurable latency within the time resolution of the system (36 ms) (Fig. 4C, D). Finally, in patch-clamp recordings, superfusion of sperm with cAMP enhanced ...
Context 3
... (Fig. 4A, B). The cAMP-evoked Ca 2+ response was abolished in sperm that lack functional CatSper (Fig. 4A). Next, we examined the kinetics of the Ca 2+ signals evoked by 8-CPT-cAMP in a stopped-flow apparatus. Upon rapid mixing of sperm with 8-CPT-cAMP, [Ca 2+ ] i rose with no measurable latency within the time resolution of the system (36 ms) (Fig. 4C, D). Finally, in patch-clamp recordings, superfusion of sperm with cAMP enhanced monovalent CatSper currents at -80 mV and +80 mV ( Fig. 5A-C, Supplementary Fig. 1F) by 1.8 ± 0.3-fold and by 1.5 ± 0.4-fold (n = 4; HS-leak subtracted), respectively. The presence of cAMP or 8-CPTcAMP in the pipette solution did not suppress activation of ...
Citations
... by [59]). Although low ROS is essential for the onset of sperm activating processes such as capacitation [60], its increased level disturbs sperm functions, thereby leading to male infertility by mechanisms such as lipid peroxidation and DNA damage [61]. The levels of ROS are therefore precisely regulated in sperm, mainly by superoxide dismutase, which coverts superoxide to H2O2 [62], and by catalase, which decomposes H2O2 [63]. ...
Fer and its sperm and cancer specific variant, FerT, are non-receptor tyrosine kinases which play roles in cancer progression and metastasis. Recent studies have shed light on the regulatory role of these kinases in ensuring proper sperm function. Comparison of the regulatory cascades in which Fer and FerT are engaged in sperm and cancer cells presents an interesting picture, in which similar regulatory interactions of these enzymes are integrated in a similar or different regulatory context in the two cell types. These diverse compositions extend from the involvement of Fer in modulation of actin cytoskeleton integrity and function, to the unique regulatory interactions of Fer with PARP-1 and the PP1 phosphatase. Furthermore, recent findings link the metabolic regulatory roles of Fer and FerT in sperm and cancer cells. In the current review, we discuss the above detailed aspects, which portray Fer and FerT as new regulatory links between sperm and malignant cells. This perspective view can endow us with new analytical and research tools that will deepen our understanding of the regulatory trajectories and networks that govern these two multi-layered systems.
... In effect, intracellular HCO 3 − and Ca 2+ bind to sAC, thereby increasing cAMP levels, which in turn activate PKA [51,52]. The binding of cAMP to the regulatory subunits of PKA allows dissociation of the tetramer and activation of the catalytic subunit. ...
In dairy goat farming, increasing the female kid rate is beneficial to milk production and is, therefore, economically beneficial to farms. Our previous study demonstrated that alkaline incubation enriched the concentration of X-chromosome-bearing sperm; however, the mechanism by which pH affects the motility of X-chromosome-bearing sperm remains unclear. In this study, we explored this mechanism by incubating dairy goat sperm in alkaline dilutions, examining the pattern of changes in sperm internal pH and Ca2+ concentrations and investigating the role of the sAC/cAMP/PKA pathway in influencing sperm motility. The results showed that adding a calcium channel inhibitor during incubation resulted in a concentration-dependent decrease in the proportion of spermatozoa with forward motility, and the sperm sAC protein activity was positively correlated with the calcium ion concentration (r = 0.9972). The total motility activity, proportion of forward motility, and proportion of X-chromosome-bearing sperm decreased (p < 0.05) when cAMP/PKA protease activity was inhibited. Meanwhile, the enrichment of X-chromosome-bearing sperm by pH did not affect the sperm capacitation state. These results indicate that alkaline dilution incubation reduces Ca2+ entry into X-sperm and the motility was slowed down through the sAC/cAMP/PKA signaling pathway, providing a theoretical foundation for further optimization of the sex control method.
... Overall, sperm motility was the main parameter impacted by incubation in the presence of EtOH and DMSO. Although we did not investigate the molecular pathways involved in the impact of the solvents on sperm motility, the very quick effect observed with EtOH is reminiscent of an unspecific action on ion channels, such as Catsper, as shown for many drugs [69][70][71]. Indeed, Catsper regulates the intracellular calcium concentration and, thereby, sperm motility [72,73]. ...
To study mechanisms involved in fertility, many experimental assays are conducted by incubating spermatozoa in the presence of molecules dissolved in solvents such as ethanol (EtOH) or dimethyl sulfoxide (DMSO). Although a vehicle control group is usually included in such studies, it does not allow to evaluate the intrinsic effect of the solvent on sperm parameters and its potential influence on the outcome of the experiment. In the present study, we incubated human spermatozoa for 4 h in a capacitation medium in the absence or the presence of different concentrations of EtOH and DMSO (0.1, 0.5, 1.0, and 2.0%) to assess the impact of these solvents on sperm motility, vitality, capacitation, and acrosome integrity. The presence of statistically significant relationships between increasing solvent concentrations and the investigated parameters was assessed using linear mixed models. A significant effect was observed with both solvents for total and progressive sperm motilities. We also evaluated the effect of time for these parameters and showed that the influence of the solvents was stable between 0 and 4 h, indicating an almost direct impact of the solvents. While EtOH did not influence sperm vitality and acrosome integrity, a significant effect of increasing DMSO concentrations was observed for these parameters. Finally, regarding capacitation, measured via phosphotyrosine content, although a dose-dependent effect was observed with both solvents, the statistical analysis did not allow to precisely evaluate the intensity of the effect. Based on the results obtained in the present study, and the corresponding linear mixed models, we calculated the concentration of both solvents which would result in a 5% decline in sperm parameters. For EtOH, these concentrations are 0.9, 0.7, and 0.3% for total motility, progressive motility, and capacitation, respectively, while for DMSO they are 1.5, 1.1, >2, 0.3 and >2% for total motility, progressive motility, vitality, capacitation, and acrosome integrity, respectively. We recommend using solvent concentrations below these values to dissolve molecules used to study sperm function in vitro, to limit side effects.
... Calcium influx is mainly driven by sperm-specific pH sensitive voltage-gated Ca 2+ channels (CatSper) [26,27]. Due to their biological relevance for male fertility, the structure, localization, types, expression, and regulation mechanisms of CatSper channels have been extensively investigated [28][29][30][31][32][33][34][35]. It is, nevertheless, worth noting that the sperm plasma membrane also has other channels, such as Ca 2+ transporters, which participate in the calcium rise during sperm capacitation (e.g., Ca 2+ -ATPases; [36,37]; transient-receptor potential (TRP) channels [38,39]; Na + /Ca 2+ exchangers (NCX) [37,40]; voltage-gated Ca 2+ channels (Ca V ) [41]; and cyclic nucleotide-gated (CNG) channels [42]). ...
Alkalinization of sperm cytosol is essential for plasma membrane hyperpolarization, hyperactivation of motility, and acrosomal exocytosis during sperm capacitation in mammals. The plasma membrane of sperm cells contains different ion channels implicated in the increase of internal pH (pHi) by favoring either bicarbonate entrance or proton efflux. Bicarbonate transporters belong to the solute carrier families 4 (SLC4) and 26 (SLC26) and are currently grouped into Na+/HCO3− transporters and Cl−/HCO3− exchangers. Na+/HCO3− transporters are reported to be essential for the initial and fast entrance of HCO3− that triggers sperm capacitation, whereas Cl−/HCO3− exchangers are responsible for the sustained HCO3− entrance which orchestrates the sequence of changes associated with sperm capacitation. Proton efflux is required for the fast alkalinization of capacitated sperm cells and the activation of pH-dependent proteins; according to the species, this transport can be mediated by Na+/H+ exchangers (NHE) belonging to the SLC9 family and/or voltage-gated proton channels (HVCN1). Herein, we discuss the involvement of each of these channels in sperm capacitation and the acrosome reaction.
... 16 However, other observations suggested that CatSper is not activated by cAMP/PKA signaling but is directly affected by chemicals used to probe the action of cAMP and PKA. 62,71 This conclusion was obtained in experiments using human sperm and, due to the observations stated above, this would not be the case in mice. In this report, we obtain similar results in terms of CatSper function and cAMP-dependent pathways. ...
The CatSper cation channel is essential for sperm capacitation and male fertility. The multi-subunit CatSper complexes form highly organized calcium signaling nanodomains on flagellar membranes. Here we report identification of an uncharacterized protein C2CD6 as a novel subunit of the CatSper complex. C2CD6 contains a calcium-dependent membrane targeting C2 domain. C2CD6 associates with the CatSper calcium-selective core forming subunits. Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male sterility. C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both in vitro and in vivo. CatSper currents are present but at a significantly lower level in C2CD6-deficient sperm. Transient treatments with either Ca2+ ionophore, starvation, or a combination of both restore the fertilization capacity of C2CD6-deficient sperm. C2CD6 interacts with EFCAB9, a pH-dependent calcium sensor in the CatSper complex. We postulate that C2CD6 facilitates incorporation of the CatSper complex into the flagellar plasma membrane and may function as a calcium sensor. The identification of C2CD6 may enable the long-sought reconstitution of the CatSper ion channel complex in a heterologous system for male contraceptive development.
... Mutations or deletions of CATSPER genes leading to loss of CatSper function are associated with male infertility (Avidan et al., 2003;Avenarius et al., 2009;Hildebrand et al., 2010;Smith et al., 2013;Jaiswal et al., 2014;Williams et al., 2015;Brown et al., 2018;Luo et al., 2019;Schiffer et al., 2020). In the past decade, a series of studies, including our own, revealed that CatSper is affected by synthetic chemicals including EDCs, odorants as well as diverse compounds used to manipulate enzymes, receptors, and ion channels Strünker et al., 2011;Brenker et al., 2012;Tavares et al., 2013;Schiffer et al., 2014;Rehfeld et al., 2016Rehfeld et al., , 2017Brenker et al., 2018;Rennhack et al., 2018;McBrinn et al., 2019;Wang et al., 2020;Zhang et al., 2020). The chemicals act as full or partial CatSper agonists, inhibitors, or feature rather a dual agonistic and inhibitory action at low and high concentrations, respectively. ...
... This demonstrates that the pharmacology of CatSper is highly complex, involving several so far unknown activatorand inhibitor-binding sites, which might be allosterically coupled. It seems that some drugs can bind to more than one of these binding sites at the same time, leading to complex pharmacological effects on CatSper and, thereby, [Ca 2þ ] i (see, e.g., Rennhacket al., 2018;Wang et al., 2020). ...
STUDY QUESTION
Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?
SUMMARY ANSWER
The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.
WHAT IS KNOWN ALREADY
In human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown.
STUDY DESIGN, SIZE, DURATION
We studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test.
MAIN RESULTS AND THE ROLE OF CHANCE
Several SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media.
LIMITATIONS, REASONS FOR CAUTION
This is an in vitro study. Future studies have to assess the physiological relevance in vivo.
WIDER IMPLICATIONS OF THE FINDINGS
The off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l’Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen’s Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.
TRIAL REGISTRATION NUMBER
NA.
... We wanted to determine whether PKA was required for the [Ca 2+ ] i increase in ejaculated human sperm. However, because PKI has been reported to directly inhibit human CatSper currents (47), we instead used KT5720, a PKA inhibitor that does not directly inhibit human CatSper currents (Wang et al., 2020). Pre-incubation of ejaculated human sperm with HCO 3 − in the presence of 50 µM KT5720 reduced the percentage of sperm responding from 67 to 32% (Figures 6A-D,G). ...
... Previous work from many labs has shown that HCO 3 − modulates Ca 2+ entry in mouse and human sperm (Wennemuth et al., 2003;Bedu-Addo et al., 2005;Chavez et al., 2014;Luque et al., 2018). Recently, mouse CatSper was proposed to be activated by HCO 3 − through activation of sAC and PKA (Orta et al., 2018), whereas this mechanism was thought not to apply to human CatSper (Wang et al., 2020). Our work resolves this issue by comparing CatSper activation in mouse and human sperm before and after ejaculation. ...
... In contrast with our results, Wang et al. (2020) recently reported that CatSper was not modulated by PKA. Several differences in the approach and interpretation of data could explain the different outcomes. ...
To fertilize an egg, mammalian sperm must undergo capacitation in the female genital tract. A key contributor to capacitation is the calcium (Ca2+) channel CatSper, which is activated by membrane depolarization and intracellular alkalinization. In mouse epididymal sperm, membrane depolarization by exposure to high KCl triggers Ca2+ entry through CatSper only in alkaline conditions (pH 8.6) or after in vitro incubation with bicarbonate (HCO3–) and bovine serum albumin (capacitating conditions). However, in ejaculated human sperm, membrane depolarization triggers Ca2+ entry through CatSper in non-capacitating conditions and at lower pH (< pH 7.4) than is required in mouse sperm. Here, we aimed to determine the mechanism(s) by which CatSper is activated in mouse and human sperm. We exposed ejaculated mouse and human sperm to high KCl to depolarize the membrane and found that intracellular Ca2+ concentration increased at pH 7.4 in sperm from both species. Conversely, intracellular Ca2+ concentration did not increase under these conditions in mouse epididymal or human epididymal sperm. Furthermore, pre-incubation with HCO3– triggered an intracellular Ca2+ concentration increase in response to KCl in human epididymal sperm. Treatment with protein kinase A (PKA) inhibitors during exposure to HCO3– inhibited Ca2+ concentration increases in mouse epididymal sperm and in both mouse and human ejaculated sperm. Finally, we show that soluble adenylyl cyclase and increased intracellular pH are required for the intracellular Ca2+ concentration increase in both human and mouse sperm. In summary, our results suggest that a conserved mechanism of activation of CatSper channels is present in both human and mouse sperm. In this mechanism, HCO3– in semen activates the soluble adenylyl cyclase/protein kinase A pathway, which leads to increased intracellular pH and sensitizes CatSper channels to respond to membrane depolarization to allow Ca2+ influx. This indirect mechanism of CatSper sensitization might be an early event capacitation that occurs as soon as the sperm contact the semen.
... Our findings suggest that this PKA→T-K→pYGIV axis may enhance PI3K-Akt signals and sperm motility. Because the sperm Ca 2+ channel, Catsper, exerts both spatial and temporal control over tyrosine phosphorylation as sperm acquire the capacity to fertilize Chung et al., 2014, and there is some evidence that H89 may directly inhibit Catsper (Wang et al., 2020), the contributions of a possible alternative Ca 2+ →TK→pYGIV pathway towards sperm motility cannot be ruled out. ...
... Because GIV-GEM was activated upon capacitation and remained active until the acrosome was shed ( Figure 4F), we hypothesized that GIV's GEM function may be required for the prevention of a premature cAMP surge in the sperm head, and hence, premature acrosome exocytosis. We first confirmed that cAMP is modulated by a variety of stimuli targeting Gi-(adenosine) and Gs-coupled (progesterone) GPCRs (Figure 7-figure supplement 1A), consistent with what has been observed before (Wang et al., 2020;Parinaud and Milhet, 1996). When the same studies were carried out on TAT-GIV peptide-transduced sperm, the expected degree of cAMP induction were observed once again ( Figure 7B), but TAT-GIV-WT, but not the GEM-deficient FA mutant peptides could significantly suppress the degree of cAMP surge across all stimuli tested ( Figure 7C, Figure 7-figure supplement 1B). ...
For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of conditional knockout (cKO) mice and cell-penetrating peptides, we show that GIV ( CCDC88A ), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine spermatozoa. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testis and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and shed light on a hitherto unforeseen cause of infertility in men.
... 16 However, other observations suggested that CatSper is not activated by cAMP/PKA signaling but is directly affected by chemicals used to probe the action of cAMP and PKA. 62,71 This conclusion was obtained in experiments using human sperm and, due to the observations stated above, this would not be the case in mice. In this report, we obtain similar results in terms of CatSper function and cAMP-dependent pathways. ...
Sperm acquire the ability to fertilize in a process called capacitation and undergo hyperactivation, a change in the motility pattern, which depends on Ca2+ transport by CatSper channels. CatSper is essential for fertilization and it is subjected to a complex regulation that is not fully understood. Here, we report that similar to CatSper, Cdc42 distribution in the principal piece is confined to four linear domains and this localization is disrupted in CatSper1‐null sperm. Cdc42 inhibition impaired CatSper activity and other Ca2+‐dependent downstream events resulting in a severe compromise of the sperm fertilizing potential. We also demonstrate that Cdc42 is essential for CatSper function by modulating cAMP production by soluble adenylate cyclase (sAC), providing a new regulatory mechanism for the stimulation of CatSper by the cAMP‐dependent pathway. These results reveal a broad mechanistic insight into the regulation of Ca2+ in mammalian sperm, a matter of critical importance in male infertility as well as in contraception.
... In human sperm, the sperm-specific Ca 2+ channel CatSper translates changes in the chemical microenvironment into changes of the intracellular Ca 2+ concentration ([Ca 2+ ] i ) and swimming behavior (Tamburrino et al., 2014;Brown et al., 2019;Wang et al., 2021). Aberrations of CATSPER genes, some of which were shown to result in a loss of CatSper function, are associated with male infertility (Avidan et al., 2003;Avenarius et al., 2009;Hildebrand et al., 2010;Smith et al., 2013;Jaiswal et al., 2014;Williams et al., 2015;Brown et al., 2018;Luo et al., 2019;Schiffer et al., 2020;Wang et al., 2020), indicating that CatSper serves as a central signaling knot in human sperm. Quite generally, CatSper is gated by membrane depolarization and intracellular alkalization (Kirichok et al., 2006;Lishko et al., 2010;Seifert et al., 2015;Hwang et al., 2019). ...
... 2017). Supporting this notion and indicating that CatSper also mediates the signals induced by SF, Ca 2+ signals evoked by ≤2.2% FF and <2% SF were abolished in sperm from CATSPER2deficient patients (Figures 1B,E) lacking functional CatSper channels (see Brenker et al., 2018b;Schiffer et al., 2020;Wang et al., 2020); at higher concentrations, both FF and SF evoked a residual, sustained [Ca 2+ ] i increase in CATSPER2 −/− sperm that might rest on inhibition of Ca 2+ export and/or Ca 2+ release from intracellular stores. We can, however, not exclude that the residual signal reflects an artifactual increase in the fluorescence of indicators rather than a genuine [Ca 2+ ] i response. ...
The sperm-specific Ca2+ channel CatSper registers chemical cues that assist human sperm to fertilize the egg. Prime examples are progesterone and prostaglandin E1 that activate CatSper without involving classical nuclear and G protein-coupled receptors, respectively. Here, we study the action of seminal and follicular fluid as well of the contained individual prostaglandins and steroids on the intracellular Ca2+ concentration of sperm from donors and CATSPER2-deficient patients that lack functional CatSper channels. We show that any of the reproductive steroids and prostaglandins evokes a rapid Ca2+ increase that invariably rests on Ca2+ influx via CatSper. The hormones compete for the same steroid- and prostaglandin-binding site to activate the channel, respectively. Analysis of the hormones’ structure–activity relationship highlights their unique pharmacology in sperm and the chemical features determining their effective properties. Finally, we show that Zn2+ suppresses the action of steroids and prostaglandins on CatSper, which might prevent premature prostaglandin activation of CatSper in the ejaculate, aiding sperm to escape from the ejaculate into the female genital tract. Altogether, our findings reinforce that human CatSper serves as a promiscuous chemosensor that enables sperm to probe the varying hormonal microenvironment prevailing at different stages during their journey across the female genital tract.
