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

Subject Area Pharmacology
Term from 2010 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 170440292
 
Final Report Year 2023

Final Report Abstract

Despite the importance of the acrosome reaction in sperm for successful fertilization, fundamental processes of this special form of calcium-regulated exocytosis, such as spontaneous abortive exocytosis and the release of calcium from the acrosomal vesicle to initiate multiple fusion pore formation are only partially understood. Recently, we described that the taste receptor Tas1R1, which in taste buds on the tongue is responsible to detect the taste compound monosodium L-glutamate (umami), is also expressed in mammalian sperm cells where it is involved in preventing an unintended acrosome reaction by constantly suppressing Calcium and cAMP-triggered maturation processes during the sperm’s journey towards the egg (capacitation). In the funded project, we now investigated whether those members of the bitter receptor family (Tas2Rs), which in humans are characterized by a correlation between a polymorphism and an impaired fertility, are also expressed in spermatozoa and whether they play a functional role for the spontaneous loss of the acrosomal vesicle. Using a membrane-permeable analogue of the second messenger NAADP in quantitative acrosome reaction studies the results confirmed our previous observation that two NAADP-dependent signaling pathways are operative in triggering efflux of calcium from the acrosomal vesicle. Using sperm of a TPC1 gen-deficient mouse strain, TPC1 was identified to be responsible to activate the low affinity pathway whereas results of our breeding experiments with a TPC2 and a TPC1/2 double knockout mouse strain provide evidence that TPC2 is a potential candidate to release acrosomal calcium by activating the high affinity NAADP signaling pathway. In contrast to sperm, which only have one single huge vesicle, mast cells of the immune system contain a large number of secretory granules. The release of stored inflammatory mediators, such as histamine and heparin also follows the conserved principles of calcium-regulated exocytosis (degranulation). However, necessary calcium is largely provided via the release of calcium from the endoplasmic reticulum (ER) as well as from acidic compartments such as endolysosomes. Our findings on isolated mast cells as well as the mast cell model RBL indicate that in contrast to sperm where TPC1-mediated efflux of acrosomal calcium is responsible to initiate the exocytotic event, TPC1 in mast cells is functionally involved in regulating the calcium balance between the ER and the endolysosomal system. A genetic deletion of TPC1 or a pharmacological inhibition by means of the plant alkaloid tetrandrine lead to an increased calcium concentration of the ER and in turn to an enhanced exocytosis both at the cellular level and in an allergy mouse model. Thus, pharmacological modulation of TPC1 might blaze a trail to develop new drugs against mast cell-related diseases, including allergic and anaphylactic reactions.

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