TRPV4 is the temperature-sensitive ion channel of human sperm

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Abstract

Ion channels control human sperm fertilizing ability by triggering hyperactivated motility, which is regulated by membrane potential, intracellular pH, and cytosolic calcium. Previous studies unraveled three essential ion channels that regulate these parameters: 1) the Ca²⁺ channel CatSper, 2) the K⁺ channel KSper, and 3) the H⁺ channel Hv1. However, the molecular identity of the sperm Na⁺ conductance that mediates initial membrane depolarization and, thus, triggers downstream signaling events is yet to be defined. Here, we functionally characterize DSper, the Depolarizing Channel of Sperm, as the temperature-activated channel TRPV4. It is functionally expressed at both mRNA and protein levels, while other temperature-sensitive TRPV channels are not functional in human sperm. DSper currents are activated by warm temperatures and mediate cation conductance, that shares a pharmacological profile reminiscent of TRPV4. Together, these results suggest that TRPV4 activation triggers initial membrane depolarization, facilitating both CatSper and Hv1 gating and, consequently, sperm hyperactivation.

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All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

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Nadine Mundt

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Marc Spehr

Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6616-4196
Polina V Lishko

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
lishko@berkeley.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3140-2769

Funding

National Institute of General Medical Sciences (R01GM111802)

Polina V Lishko

Pew Charitable Trusts (28642)

Polina V Lishko

Alfred P. Sloan Foundation (FR‐2015‐65398)

Polina V Lishko

Deutscher Akademischer Austauschdienst

Nadine Mundt

Packer Wentz Endowment Will

Polina V Lishko

Rose Hill Innovator Fund

Polina V Lishko

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The participation of healthy human sperm donor volunteers was approved by the Committee on Human Research at the University of California, Berkeley (protocol number 2013-06-5395). All donors provided informed consent.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.