Overexpression of SK3 Channels Dampens Uterine Contractility to Prevent Preterm Labor in Mice1

Abstract

The mechanisms that control the timing of labor have yet to be fully characterized. In a previous study, the overexpression of small conductance calcium-activated K(+) channel isoform 3 in transgenic mice, Kcnn3(tm1Jpad)/Kcnn3(tm1Jpad) (also known as SK3(T/T)), led to compromised parturition, which indicates that KCNN3 (also known as SK3) plays an important role 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. Thus, we investigated the effects of SK3 channel expression on gestation and parturition, comparing SK3(T/T) mice to wild type (WT) mice. Here, we show in WT mice that SK3 transcript and protein are significantly reduced during pregnancy. We also found the force produced by uterine strips from Pregnancy Day 19 (P19) SK3(T/T) mice was significantly less than that measured in WT or SK3 knockout control (SK3(DOX)) uterine strips, 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 complete delivery in SK3(T/T) mice within 48 h after injection. Thus, stimuli that initiate parturition under normal circumstances are insufficient to coordinate the uterine contractions needed for the 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 sufficient for delivery in both term and preterm mice.

In vivo measurement of intrauterine pressure by telemetry: a new approach for studying parturition in mouse models

“…One mouse model that exhibits compromised parturition is the SK3 T/T mouse that was used in this study (1,10). Using an in vitro approach, we previously demonstrated (10) that uterine contractions in these mice were dampened, suggesting that altered uterine function leads to dysfunctional delivery.…”

“…To test whether uterine telemetry can be used successfully to monitor labor in an induced model of preterm labor, we implanted WT mice as described above. Recordings were started on 14 dpc, and at 1:00 PM on 15 dpc the mice were injected with RU486 (100 g; Sigma, St. Louis, MO) in ethanol, as described previously (4,10). Uterine pressure was measured for 24 h.…”

“…Although the size of the radiotelemetric transmitters initially excluded use of this technology to measure intrauterine pressure in mice, the development of a miniature transmitter (1.1 cc) that can measure physiological pressure (in the range of Ϫ20 to 300 mmHg) has enabled us to develop a method that can be utilized to measure intrauterine pressure in mice. We have now applied this procedure to SK3 channel-overexpressing (SK3 T/T ) mice, in which uterine contractions are dampened, resulting in delayed or hindered delivery in 70% of dams (1,10). In addition, we further distinguished the role that SK3 channels play in the labor process.…”

Insights Into Parturition Biology From Genetically Altered Mice

“…Moreover, when administered stimuli precipitate PTL in wild-type mice, SK3-overexpressing mice do not complete labor even if serum progesterone levels decline (51). SK3 expression is decreased in both mice and humans at term (49,51), indicating an importance of regulation of this channel for parturition in both species.…”

“…SK3-overexpressing females exhibit defective parturition, manifested by prolonged delivery and mortality of pups and dams (50). Weaker contractions are observed in uterus from term SK3-overexpressing versus wild-type females (51). Moreover, when administered stimuli precipitate PTL in wild-type mice, SK3-overexpressing mice do not complete labor even if serum progesterone levels decline (51).…”