title: SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility.
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 Ca(2+) and K(+), leading to an elevation in cytosolic Ca(2+) critical for activation of hyperactivated swimming motility. In mice, the Ca(2+) conductance (alkalization-activated Ca(2+)-permeable sperm channel, CATSPER) arises from an ensemble of CATSPER subunits, whereas the K(+) conductance (sperm pH-regulated K(+) current, KSPER) arises from a pore-forming 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.
authors: Institute of Life Science, Nanchang University, Nanchang, Jiangxi, China; and.
authors: Xu-Hui
authors: XH
authors: Zeng
authors: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110.
authors: Chengtao
authors: C
authors: Yang
authors: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110.
authors: Xiao-Ming
authors: XM
authors: Xia
authors: Institute of Life Science, Nanchang University, Nanchang, Jiangxi, China; and.
authors: Min
authors: M
authors: Liu
authors: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110 clingle@morpheus.wustl.edu.
authors: Christopher J
authors: CJ
authors: Lingle
mesh_terms: D000200:Action Potentials; D000468:Alkalies; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D004822:Epididymis / Q000502:physiology; D005298:Fertility; D017353:Gene Deletion; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015640:Ion Channel Gating; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D018345:Mice, Knockout; D021122:Protein Subunits / Q000378:metabolism*; D013094:Spermatozoa / Q000378:metabolism*
chemical_list: D000468:Alkalies; D015220:Calcium Channels; C488642:Catsper1 protein, mouse; C110627:Kcnu1 protein, mouse; C569399:LRRC52 protein, mouse; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008565:Membrane Proteins; D021122:Protein Subunits; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: KSPER; SLO3 channels; auxiliary subunits; sperm fertility