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Deletion of the Slo3 gene abolishes alkalization-activated K~+ current in mouse spermatozoa

Sung Tae Kim;Christopher J.Lingle

  Mouse spermatozoa express a pH-dependent K* current(KSper) thought to be composed of subunits encoded by the Slo3 gene. However,the equivalence of KSper and Slo3-dependent current remains uncertain,because heterologous expression of Slo3 results in currents that are less effectively activated by aikaiization than are native KSper currents,Here,we show that genetic deletion of Slo3 abolishes all pH-dependent K~+ current at physiological membrane potentials in corpus epididymal sperm,A residual pH-dependent outward current(I_(ires)) is observed m Slo3~(-/-) sperm at potentials of >0 mV.Differential inhibition of KSper/Slo3 and I_(Kres) by dofilium reveals that the amplitude of I_(Kres) is similar in both wild-type(wt)and Slo3~(-/-) sperm.The properties of I_(Kres) suggest that it likely represents outward monovalent cation flux through CatSper channels.Thus,KSper. Slo3 may account for essentially all mouse sperm K~+ current and is the sole pH-dependent Kconductance in these sperm.With physiological ionic gradients, aikaiization depolarizes Slo3~(-/-) spermatozoa,presumably from CatSper activation,in contrast to Slo3/KSper-medi3ted hyperpolarization in wt sperm.Slo3~(-/-) male mice are infertile,but Slo3~(-/-) sperm exhibit some fertility within in vitro fertilization assays. Slo3~(-/-) sperm exhibit a higher incidence of morphological abnormalities accentuated by hypotonic challenge and also exhibit deficits in motility in the absence of bicarbonate,revealing a role of KSper under unstimulated conditions.Together,these results show that KSper/Slo3 is the primary spermatazoan K~+ current that KSper may play a critical role in acquisition of normal morphology and sperm motility when faced with hyperosmotic challenges, and that Slo3 is critical for fertility.……