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

Departments of Molecular Physiology and Biophysics,³ Obstetrics and Gynecology,⁴ Internal Medicine and Pharmacology,⁵ and Veterans Affairs Medical Center,⁶ University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

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.

ion channels, myometrium, parturition, pregnancy, preterm labor, SK3 channels, smooth muscle, uterus

¹Supported by the National Institutes of Health (HD-037831 to S.K.E.) and the March of Dimes (21-FY04-169 to S.K.E.).

Correspondence: ²Sarah K. England, 51 Newton Rd. BSB 6-555, University of Iowa, Iowa City, IA 52242. FAX: 319 335 7330; e-mail: Sarah-England{at}uiowa.edu