The role and regulation of small conductance CA2+ activated K+ channel subtype 3 in myometrial contraction and placental development

Abstract

Mechanisms that control the timing of labor have yet to be fully characterized. In a previous study (8), over-expression of small conductance calcium-activated K channel subtype 3 in transgenic mice, Kcnn3/Kcnn3 (also known as SK3), led to compromised parturition, which demonstrated the important role of KCNN3 in the delivery process. Based on these findings, we hypothesized that SK3 channel expression must be downregulated late in pregnancy to enable the uterus to produce the forceful contractions required for parturition. To test this hypothesis we investigated the effects of SK3 channel expression on gestation and parturition, comparing SK3 mice to WT. In WT mice, SK3 transcript and protein were significantly reduced during pregnancy. The force produced by uterine strips from P19 SK3 mice was significantly less than that measured in uterine strips from WT or SK3 mice, and this effect was reversed by application of the SK3 channel inhibitor apamin. Moreover, two treatments that induce labor in mice failed to result in delivery within 48 hours following injection on P15 in SK3 mice. Thus, stimuli that initiate parturition under normal circumstances are insufficient to coordinate the uterine contractions needed for completion of delivery when SK3 channel activity is in excess. Our data indicate that SK3 channels must be downregulated for the gravid uterus to generate labor contractions, which are sufficient for delivery, in both term and preterm mice. Introduction Throughout gestation the uterus is maintained in a quiescent state to allow fetal growth and development. Eventually, the relaxed uterus transitions to an active state,