دورية أكاديمية
A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function.
| العنوان: | A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function. |
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| المؤلفون: | Lyon M; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Li P; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Ferreira JJ; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Lazarenko RM; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232., Kharade SV; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232., Kramer M; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232., McClenahan SJ; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232., Days E; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232., Bauer JA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232., Spitznagel BD; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Weaver CD; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Borrego Alvarez A; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Puga Molina LC; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Lybaert P; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110.; Laboratoire de recherche en Reproduction humaine, Université Libre de Bruxelles, Bruxelles 1050, Belgium., Khambekar S; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Liu A; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110., Lindsley CW; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232.; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Denton J; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232.; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232., Santi CM; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jan 24; Vol. 120 (4), pp. e2212338120. Date of Electronic Publication: 2023 Jan 17. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Infertility, Male* , Large-Conductance Calcium-Activated Potassium Channels*/antagonists & inhibitors, Humans ; Male ; Membrane Potentials/physiology ; Semen ; Spermatozoa/physiology |
| مستخلص: | To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining the molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods and detecting causes of idiopathic male infertility. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K + ) channel SLO3 [C. M. Santi et al. , FEBS Lett. 584 , 1041-1046 (2010)]. In human sperm, it has long been unclear whether hyperpolarization depends on SLO3 or the ubiquitous K + channel SLO1 [N. Mannowetz, N. M. Naidoo, S. A. S. Choo, J. F. Smith, P. V. Lishko, Elife 2 , e01009 (2013), C. Brenker et al. , Elife 3 , e01438 (2014), and S. A. Mansell, S. J. Publicover, C. L. R. Barratt, S. M. Wilson, Mol. Hum. Reprod. 20 , 392-408 (2014)]. In this work, we identified the first selective inhibitor for human SLO3-VU0546110-and showed that it completely blocked heterologous SLO3 currents and endogenous K + currents in human sperm. This compound also prevented sperm from hyperpolarizing and undergoing hyperactivated motility and induced acrosome reaction, which are necessary to fertilize an egg. We conclude that SLO3 is the sole K + channel responsible for hyperpolarization and significantly contributes to the fertilizing ability of human sperm. Moreover, SLO3 is a good candidate for contraceptive development, and mutation of this gene is a possible cause of idiopathic male infertility. |
| التعليقات: | Comment in: Proc Natl Acad Sci U S A. 2023 Feb 21;120(8):e2221758120. (PMID: 36791103) |
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| معلومات مُعتمدة: | R01 HD069631 United States HD NICHD NIH HHS; R33 HD099742 United States HD NICHD NIH HHS; R50 CA211206 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: SLO3; capacitation; drug discovery; human sperm; ion channels |
| المشرفين على المادة: | 0 (Large-Conductance Calcium-Activated Potassium Channels) 0 (KCNU1 protein, human) |
| تواريخ الأحداث: | Date Created: 20230117 Date Completed: 20230120 Latest Revision: 20231221 |
| رمز التحديث: | 20231221 |
| مُعرف محوري في PubMed: | PMC9942793 |
| DOI: | 10.1073/pnas.2212338120 |
| PMID: | 36649421 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2212338120 |