TY - JOUR
T1 - Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization
AU - Balbach, Melanie
AU - Ghanem, Lubna
AU - Rossetti, Thomas
AU - Kaur, Navpreet
AU - Ritagliati, Carla
AU - Ferreira, Jacob
AU - Krapf, Dario
AU - Puga Molina, Lis C.
AU - Santi, Celia Maria
AU - Hansen, Jan Niklas
AU - Wachten, Dagmar
AU - Fushimi, Makoto
AU - Meinke, Peter T.
AU - Buck, Jochen
AU - Levin, Lonny R.
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: [email protected].
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.
AB - Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.
KW - acrosome reaction
KW - capacitation
KW - contraception
KW - cyclic AMP
KW - sperm motility
UR - http://www.scopus.com/inward/record.url?scp=85117107611&partnerID=8YFLogxK
U2 - 10.1093/molehr/gaab054
DO - 10.1093/molehr/gaab054
M3 - Article
C2 - 34463764
AN - SCOPUS:85117107611
SN - 1360-9947
VL - 27
SP - 1
EP - 13
JO - Molecular human reproduction
JF - Molecular human reproduction
IS - 9
ER -