SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility

Xu Hui Zeng, Chengtao Yang, Xiao Ming Xia, Min Liua, Christopher J. Lingle

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Following entry into the female reproductive tract, mammalian sperm undergo a maturation process termed capacitation that results in competence to fertilize ova. Associated with capacitation is an increase in membrane conductance to both Ca2+ and K+, leading to an elevation in cytosolic Ca2+ critical for activation of hyperactivated swimming motility. In mice, the Ca2+ conductance (alkalization-activated Ca2+-permeable sperm channel, CATSPER) arises from an ensemble of CATSPER subunits, whereas the K+ conductance (spermpH-regulated K+ current, KSPER) arises froma poreforming ion channel subunit encoded by the slo3 gene (SLO3) subunit. In the mouse, both CATSPER and KSPER are activated by cytosolic alkalization and a concerted activation of CATSPER and KSPER is likely a common facet of capacitation-associated increases in Ca 2+ and K + conductance among various mammalian species. The properties of heterologously expressed mouse SLO3 channels differ from native mouse KSPER current. Recently, a potential KSPER auxiliary subunit, leucine-rich-repeat-containing protein 52 (LRRC52), was identified in mouse sperm and shown to shift gating of SLO3 to be more equivalent to native KSPER. Here, we show that genetic KO of LRRC52 results in mice with severely impaired fertility. Activation of KSPER current in sperm lacking LRRC52 requires more positive voltages and higher pH than for WT KSPER. These results establish a critical role of LRRC52 in KSPER channels and demonstrate that loss of a non-pore-forming auxiliary subunit results in severe fertility impairment. Furthermore, through analysis of several genotypes that influence KSPER current properties we show that in vitro fertilization competence correlates with the net KSPER conductance available for activation under physiological conditions.

Original languageEnglish
Pages (from-to)2599-2604
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number8
DOIs
StatePublished - Feb 24 2015

Keywords

  • Auxiliary subunits
  • KSPER
  • SLO3 channels
  • Sperm fertility

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