The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm
The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiologic...
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1221578/full |
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| author | Lydia Wehrli Lydia Wehrli Ioannis Galdadas Ioannis Galdadas Lionel Voirol Martin Smieško Martin Smieško Yves Cambet Vincent Jaquet Stéphane Guerrier Stéphane Guerrier Francesco Luigi Gervasio Francesco Luigi Gervasio Francesco Luigi Gervasio Francesco Luigi Gervasio Serge Nef Serge Nef Rita Rahban Rita Rahban |
| author_facet | Lydia Wehrli Lydia Wehrli Ioannis Galdadas Ioannis Galdadas Lionel Voirol Martin Smieško Martin Smieško Yves Cambet Vincent Jaquet Stéphane Guerrier Stéphane Guerrier Francesco Luigi Gervasio Francesco Luigi Gervasio Francesco Luigi Gervasio Francesco Luigi Gervasio Serge Nef Serge Nef Rita Rahban Rita Rahban |
| author_sort | Lydia Wehrli |
| collection | DOAJ |
| description | The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur. |
| first_indexed | 2024-03-12T22:50:59Z |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-12T22:50:59Z |
| publishDate | 2023-07-01 |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-615465c0b9f74934804518fb5b8517a12023-07-20T11:29:42ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-07-011110.3389/fcell.2023.12215781221578The action of physiological and synthetic steroids on the calcium channel CatSper in human spermLydia Wehrli0Lydia Wehrli1Ioannis Galdadas2Ioannis Galdadas3Lionel Voirol4Martin Smieško5Martin Smieško6Yves Cambet7Vincent Jaquet8Stéphane Guerrier9Stéphane Guerrier10Francesco Luigi Gervasio11Francesco Luigi Gervasio12Francesco Luigi Gervasio13Francesco Luigi Gervasio14Serge Nef15Serge Nef16Rita Rahban17Rita Rahban18Department of Genetic Medicine and Development, University of Geneva, Geneva, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandInstitute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandResearch Center for Statistics, Geneva School of Economics and Management, University of Geneva, Geneva, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandDepartment of Pharmaceutical Sciences, University of Basel, Basel, SwitzerlandReaders, Assay Development and Screening Unit (READS Unit), Faculty of Medicine, University of Geneva, Geneva, SwitzerlandReaders, Assay Development and Screening Unit (READS Unit), Faculty of Medicine, University of Geneva, Geneva, SwitzerlandResearch Center for Statistics, Geneva School of Economics and Management, University of Geneva, Geneva, SwitzerlandFaculty of Science, University of Geneva, Geneva, SwitzerlandInstitute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandDepartment of Chemistry, University College London, London, United Kingdom0Institute of Structural and Molecular Biology, University College London, London, United KingdomDepartment of Genetic Medicine and Development, University of Geneva, Geneva, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandDepartment of Genetic Medicine and Development, University of Geneva, Geneva, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandThe sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur.https://www.frontiersin.org/articles/10.3389/fcell.2023.1221578/fullCatSpersteroidshuman spermhigh-throughput screeningcalcium signalingpharmacophore modelling |
| spellingShingle | Lydia Wehrli Lydia Wehrli Ioannis Galdadas Ioannis Galdadas Lionel Voirol Martin Smieško Martin Smieško Yves Cambet Vincent Jaquet Stéphane Guerrier Stéphane Guerrier Francesco Luigi Gervasio Francesco Luigi Gervasio Francesco Luigi Gervasio Francesco Luigi Gervasio Serge Nef Serge Nef Rita Rahban Rita Rahban The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm Frontiers in Cell and Developmental Biology CatSper steroids human sperm high-throughput screening calcium signaling pharmacophore modelling |
| title | The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm |
| title_full | The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm |
| title_fullStr | The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm |
| title_full_unstemmed | The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm |
| title_short | The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm |
| title_sort | action of physiological and synthetic steroids on the calcium channel catsper in human sperm |
| topic | CatSper steroids human sperm high-throughput screening calcium signaling pharmacophore modelling |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1221578/full |
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