Chemosensory signal transduction in human sperm

• Applicant: Professor Dr. Timo Strünker
• Subject Area: Cell Biology ; Reproductive Medicine, Urology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 420653497

In the oviduct cumulus cells surrounding the oocyte release progesterone. In human sperm, progesterone activates the sperm-specific Ca2+ channel CatSper by a non-genomic mechanism. The ensuing Ca2+ increase controls chemotaxis, hyperactivation, and acrosomal exocytosis of sperm and, thereby, orchestrates the fertilization process. The progesterone-induced Ca2+ signal consists of a rapid Ca2+ transient followed by a slower, sustained Ca2+ elevation. Both the transient and sustained phase of the Ca2+ signal rest on Ca2+ influx via CatSper. The mechanisms shaping the Ca2+ response are, however, unknown. In particular, the mechanism that curtails Ca2+ influx via CatSper has remained elusive. We proposed that this might involve an interplay between CatSper and the sperm-specific Ca2+-activated K+ channel Slo3: Ca2+ influx via CatSper might activate Slo3 and the ensuing Ca2+-induced hyperpolarization decreases the open probability of CatSper, curtailing the Ca2+ influx. In this research endeavor, we want to scrutinize this model. To this end, we want to investigate by optical methods progesterone-induced changes of human sperm´s membrane voltage (Vm) using fast voltage-sensitive dyes and kinetic stopped-flow fluorimetry. To study the interplay of CatSper and Slo3, to elucidate whether and how Ca2+ and Vm signaling is interconnected, and to delineate the sequence of events, we will simultaneously monitor progesterone-evoked Ca2+ and Vm responses by fluorescence multiplexing. Preliminary data obtained with this technique strongly support the notion that Vm and Ca2+ signaling are intimately entangled in human sperm and that Slo3 is a critical determinant of the non-genomic progesterone-signaling pathway.

• DFG Programme: Research Grants