The acrosome reaction in sperm: A special type of regulated exocytosis

• Applicant: Privatdozentin Dr. Ingrid Boekhoff, Ph.D.
• Subject Area: Pharmacology
• Term: from 2010 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 170440292

One special feature of the acrosome reaction is that the lysosome-related acrosomal vesicle in the sperm head supplies Ca2+ for its own exocytosis. Investigating whether the recently described endo-lysosomal Ca2+ release channels of the two pore channel (TPC) family are expressed in mammalian spermatozoa, and whether their potential activator NAADP contributes to acrosomal secretion we found that two independent NAADP-dependent pathways cause acrosomal exocytosis, where TPC1 was found to be responsible for activating the low affinity cascade. Since our results also provide evidence for an expression of TPC2, we will now examine whether TPC2 is responsible to activate the high affinity NAADP signaling pathway, and whether a simultaneous genetic deletion of TPC1 and TPC2 affects Zona pellucida induced fusion of the acrosome and breeding successful of the animals. However, since our previous study also uncovered a possible functional cross talk between the acrosomal IP3R and TPCs, we will also investigate whether a co-stimulation of TPCs enhances an IP3 evoked Ca2+ increase in a synergistic or in an additive manner, and whether IRBIT, an inhibitor of the IP3R, which we recently identified in mammalian spermatozoa, has any impact on acrosomal secretion.During their long distant journey of ejaculated sperm to the mature egg in the oviduct, sperm are exposed to progressively changing concentrations of different chemical compounds whose recognition capacity is directly linked to the sperm`s ability to interact with the Zona pellucida surrounding the oocyte. However, our current knowledge about the molecular identity of appropriate chemosensory receptor proteins which recognize changes in pH, but also gradients of different sugars, amino acids or hormones is still rudimental. In this context, the recent discovery of an ectopic expression of taste receptors is worth mentioning, which in taste buds on the tongue are known to detect a broad spectrum of compounds with different chemical properties. Examining the expression of taste receptors in male germ cells we found that the two binding partners, which form the functional umami receptor (Tas1R1/Tas1R3, Monosodium L-Glutamat), and components of the coupled taste transduction cascade, like the G protein alpha subunit Gustducin and the cation channel TRPM5 are expressed in sperm from mice to humans. In addition, using sperm of a Tas1R1 deficient mouse strain, a significant elevation of the spontaneous acrosome reaction rate was detected. However, whether Tas1R3, Gustducin and TRPM5 also affect acrosomal secretion, is not yet clear, although it has been demonstrated that a simultaneous genetic absence of both, Tas1R3 and Gustducin renders knock-out males sterile. Therefore, we will systematically examine the functional relationship between the efficiency of acrosome reaction and Tas1Rs, Gustducin and TRPM5 in mouse as well as in human sperm.

• DFG Programme: Research Grants