Ovulation is triggered by a cyclical modulation of gonadotropes into a hyperexcitable state
Viktoria Götz,
Sen Qiao,
Debajyoti Das,
Philipp Wartenberg,
Amanda Wyatt,
Vanessa Wahl,
Igor Gamayun,
Samer Alasmi,
Claudia Fecher-Trost,
Markus R. Meyer,
Roland Rad,
Thorsten Kaltenbacher,
Kathrin Kattler,
Peter Lipp,
Ute Becherer,
Patrice Mollard,
Michael Candlish,
Ulrich Boehm
Affiliations
Viktoria Götz
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Sen Qiao
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Debajyoti Das
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Philipp Wartenberg
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Amanda Wyatt
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Vanessa Wahl
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Igor Gamayun
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Samer Alasmi
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Claudia Fecher-Trost
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Markus R. Meyer
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Roland Rad
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich 80333, Germany
Thorsten Kaltenbacher
Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich 80333, Germany
Kathrin Kattler
Department of Genetics and Epigenetics, Saarland University, Saarbrücken 66123, Germany
Peter Lipp
Molecular Cell Biology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Ute Becherer
Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University School of Medicine, Homburg 66421, Germany
Patrice Mollard
IGF, CNRS, INSERM, University of Montpellier, Montpellier 34090, France
Michael Candlish
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany
Ulrich Boehm
Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg 66421, Germany; Corresponding author
Summary: Gonadotropes in the anterior pituitary gland are essential for fertility and provide a functional link between the brain and the gonads. To trigger ovulation, gonadotrope cells release massive amounts of luteinizing hormone (LH). The mechanism underlying this remains unclear. Here, we utilize a mouse model expressing a genetically encoded Ca2+ indicator exclusively in gonadotropes to dissect this mechanism in intact pituitaries. We demonstrate that female gonadotropes exclusively exhibit a state of hyperexcitability during the LH surge, resulting in spontaneous [Ca2+]i transients in these cells, which persist in the absence of any in vivo hormonal signals. L-type Ca2+ channels and transient receptor potential channel A1 (TRPA1) together with intracellular reactive oxygen species (ROS) levels ensure this state of hyperexcitability. Consistent with this, virus-assisted triple knockout of Trpa1 and L-type Ca2+ subunits in gonadotropes leads to vaginal closure in cycling females. Our data provide insight into molecular mechanisms required for ovulation and reproductive success in mammals.
