TY - JOUR
T1 - A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function
AU - Lyon, Maximilian
AU - Li, Ping
AU - Ferreira, Juan J.
AU - Lazarenko, Roman M.
AU - Kharade, Sujay V.
AU - Kramer, Meghan
AU - McClenahan, Samantha J.
AU - Days, Emily
AU - Bauer, Joshua A.
AU - Spitznagel, Brittany D.
AU - Weaver, C. David
AU - Alvarez, Aluet Borrego
AU - Puga Molina, Lis C.
AU - Lybaert, Pascale
AU - Khambekar, Saayli
AU - Liu, Alicia
AU - Lindsley, Craig W.
AU - Denton, Jerod
AU - Santi, Celia M.
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by grants from the National Institutes of Health (R01 HD069631 to C.M.S., and R33 HD099742 to C.M.S. and J.D.) and the Male Contraceptive Initiative (2019-B01 to M.L.). The authors thank Deborah J. Frank for editing the manuscript, Dr. Ali Ahmady, Lab Directior of Reproductive Endocrinology and Infertility at Washington University for facilitating the collection of human samples, and Dr. Paul H. Schlesinger, Associate Professor of Cell Biology & Physiology at Washington University for use of the spectrophotometer.
Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/1/24
Y1 - 2023/1/24
N2 - 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.
AB - 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.
KW - SLO3
KW - capacitation
KW - drug discovery
KW - human sperm
KW - ion channels
UR - http://www.scopus.com/inward/record.url?scp=85146403939&partnerID=8YFLogxK
U2 - 10.1073/pnas.2212338120
DO - 10.1073/pnas.2212338120
M3 - Article
C2 - 36649421
AN - SCOPUS:85146403939
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
M1 - e2212338120
ER -