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

Leonie Herrmann, Christoph Brenker, Timo Strünker, Teresa Mittermair, Vesna Bojovic, Jens Münchow, W Felix Zhu, Carla Trugge, David Fußhöller, Jan Jikeli, Louisa Temme, U Benjamin Kaupp

Journal: British journal of pharmacology 2025;182(12):2694-2712

PMID: 40016153

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Abstract

BACKGROUND AND PURPOSE

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

EXPERIMENTAL APPROACH

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

KEY RESULTS

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

CONCLUSIONS AND IMPLICATIONS

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

Address: Centre of Reproductive Medicine and Andrology, University Hospital Münster, University of Münster, Münster, Germany.; Centre of Medical Genetics, Institute of Reproductive Genetics, University of Münster, Münster, Germany.; Centre of Reproductive Medicine and Andrology, University Hospital Münster, University of Münster, Münster, Germany.; Centre of Reproductive Medicine and Andrology, University Hospital Münster, University of Münster, Münster, Germany.; GRK 2515, Chemical Biology of Ion Channels (Chembion), University of Münster, Münster, Germany.; GRK 2515, Chemical Biology of Ion Channels (Chembion), University of Münster, Münster, Germany.; Institute of Pharmaceutical and Medicinal Chemistry, Pharmacampus, University of Münster, Münster, Germany.; Molecular Sensory Systems, Max Planck Institute for Neurobiology of Behavior - caesar, Bonn, Germany.; GRK 2515, Chemical Biology of Ion Channels (Chembion), University of Münster, Münster, Germany.; Institute of Pharmacy, University of Hamburg, Hamburg, Germany.; Molecular Sensory Systems, Max Planck Institute for Neurobiology of Behavior - caesar, Bonn, Germany.; Life and Medical Sciences Institute (LIMES), University Bonn, Bonn, Germany.; Centre of Reproductive Medicine and Andrology, University Hospital Münster, University of Münster, Münster, Germany.; GRK 2515, Chemical Biology of Ion Channels (Chembion), University of Münster, Münster, Germany.; Cells in Motion Interfaculty Centre, University of Münster, Münster, Germany.

DOI: 10.1111/bph.70009

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MeSH Terms: Humans, Male, Spermatozoa, Calcium Channels, Calcium, Plasma Membrane Calcium-Transporting ATPases, Calcium Signaling, Cell Membrane, Adult