SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility.
نویسندگان
چکیده
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.
منابع مشابه
LRRC52 (leucine-rich-repeat-containing protein 52), a testis-specific auxiliary subunit of the alkalization-activated Slo3 channel.
KSper, a pH-dependent K(+) current in mouse spermatozoa that is critical for fertility, is activated by alkalization in the range of pH 6.4-7.2 at membrane potentials between -50 and 0 mV. Although the KSper pore-forming subunit is encoded by the Slo3 gene, heterologously expressed Slo3 channels are largely closed at potentials negative to 0 mV at physiological pH. Here we identify a Slo3-assoc...
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Plasma membrane hyperpolarization associated with activation of Ca2+-activated K+ channels plays an important role in sperm capacitation during fertilization. Although Slo3 (slowpoke homologue 3), together with the auxiliary γ2-subunit, LRRC52 (leucine-rich-repeat-containing 52), is known to mediate the pH-sensitive, sperm-specific K+ current KSper in mice, the molecular identity of this channe...
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During passage through the female reproductive tract, mammalian sperm undergo a maturation process termed capacitation that renders sperm competent to produce fertilization. Capacitation involves a sequence of changes in biochemical and electrical properties, the onset of a hyperactivated swimming behavior, and development of the ability to undergo successful fusion and penetration with an egg....
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BACKGROUND The pH and voltage-regulated Slo3 K(+) channel, a homologue of the Ca(2+)- and voltage-regulated Slo1 K(+) channel, is thought to be primarily expressed in sperm, but the properties of Slo3 studied in heterologous systems differ somewhat from the native sperm KSper pH-regulated current. There is the possibility that critical partners that regulate Slo3 function remain unidentified. T...
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BACKGROUND AND PURPOSE The Slo3 (KCa 5.1) channel is a major component of mammalian KSper (sperm potassium conductance) channels and inhibition of these channels by quinine and barium alters sperm motility. The aim of this investigation was to determine the mechanism by which these drugs inhibit Slo3 channels. EXPERIMENTAL APPROACH Mouse (m) Slo3 (KCa 5.1) channels or mutant forms were expres...
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ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 112 8 شماره
صفحات -
تاریخ انتشار 2015