Chemosensory signalling in human sperm is controlled by Ca2+ influx via CatSper and Ca2+ clearance via plasma membrane Ca2+ ATPases

Abstract

Background and purpose: Loss of function of the sperm-specific Ca²⁺ channel CatSper is a common channelopathy that causes male infertility. CatSper controls the intracellular Ca²⁺ concentration and, thereby, the motility of human sperm. Activation of CatSper by oviductal ligands evokes a transient Ca²⁺ increase, which entails changes in the flagellar beat that are required for fertilisation. The CatSper-mediated Ca²⁺ influx has been studied extensively, whereas the mechanisms underlying Ca²⁺ clearance and recovery from Ca²⁺ influx have remained ill-defined.

Experimental approach: We examined how pharmacological suppression of Ca²⁺ export from the cytosol into the extracellular space or Ca²⁺ uptake into intracellular stores affects the resting Ca²⁺ concentration and CatSper-mediated Ca²⁺ signals in human sperm. We studied sperm of healthy volunteers and infertile men lacking functional CatSper channels, using kinetic Ca²⁺- and pH-fluorometry as well as patch-clamp recordings.

Key results: We show that Ca²⁺ entering human sperm via CatSper is predominantly, if not exclusively, exported by plasma membrane Ca²⁺ ATPases (PMCAs). Na⁺/Ca²⁺ exchange and Ca²⁺ uptake into intracellular stores or mitochondria play no or only a negligible role in Ca²⁺ clearance in human sperm.

Conclusions and implications: Ca²⁺ signalling in human sperm is controlled by the functional interplay of CatSper and PMCAs, that is, the balance between Ca²⁺ influx and Ca²⁺ export that is required for human sperm function and fertilisation.

Keywords: Ca2+ signaling; CatSper; PMCA; human sperm.