Acetylcholine and nicotinic receptors in the ovary

• Applicants: Dr. Thomas Fröhlich; Privatdozent Dr. Lars Kunz; Professor Dr. Artur Mayerhofer
• Subject Area: Reproductive Medicine, Urology ; Gynaecology and Obstetrics
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432434245

Although known mainly as a neurotransmitter, acetycholine (ACh) has been recognized to be produced by non-neuronal cells throughout the body, where it has additional roles (“non-neuronal cholinergic systems”). An important emerging function is its ability to regulate inflammatory processes. Our previous work has explored ACh in the female gonad, the ovary. In brief, we have used a combination of cellular studies, employing human IVF-derived granulosa cells (GCs), as a window into the human ovary, and systemic approaches (in rat), as well as 3D culture of nonhuman primate follicles. The data obtained support the hypothesis that ACh acts as a trophic factor for human GCs in culture and in situ, in the ovarian follicle. ACh-esterase-blockage, by the drug huperzine A (HupA) elevated ACh levels and enhanced follicular growth and fertility in rat and improved follicle development in 3D cultures of nonhuman primate ovarian follicles. Related work also revealed that necroptosis, a form of regulated cell death, is linked to ACh-esterase and is important for the fate of follicles and the corpus luteum, specifically in human/nonhuman primates. Furthermore, actions of atropine indicated that CHRMs (= muscarinic ACh-receptors) are involved in mediating growth-promoting actions of ACh. Newly available data and our pilot studies pinpoint, however, also that in other, yet related aspects of ACh actions, nicotinic ACh-receptors, mainly CHRNA7, are involved. We therefore put forward an extended hypothesis, namely that ACh actions on GCs and ovarian functions also involve nicotinic receptors (i.e. CHRNA7), which link ACh to the regulation of inflammatory events in the ovary. We also hypothesize that inflammatory events are involved in cell death events, including necroptosis, in the ovary (follicular atresia and corpus luteum regression). Cellular and molecular studies, proteomic and transcriptomic analyses, involving human GCs, human GC tumor-derived KGN, as well as systemic studies in adequate animal models (3D culture of nonhuman primate follicles; rat) will address these points. We build on established national and international collaborations and expect results of translational importance.

• DFG Programme: Research Grants