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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Myometrial expression of small conductance Ca²⁺-activated K⁺ channels depresses phasic uterine contraction

¹Department of Physiology, University of South Alabama College of Medicine, Mobile, Alabama; and ²Vollum Institute, Oregon Health Sciences University, Portland, Oregon

Submitted 15 May 2006 ; accepted in final form 18 September 2006

Mechanisms regulating uterine contractility are poorly understood. We hypothesized that a specific isoform of small conductance Ca²⁺-activated K⁺ (SK) channel, SK3, promotes feedback regulation of myometrial Ca²⁺ and hence relaxation of the uterus. To determine the specific functional impact of SK3 channels, we assessed isometric contractions of uterine strips from genetically altered mice (SK3^T/T), in which SK3 is overexpressed and can be suppressed by oral administration of doxycycline (SK3^T/T+Dox). We found SK3 protein in mouse myometrium, and this expression was substantially higher in SK3^T/T mice and lower in SK3^T/T+Dox mice compared with wild-type (WT) controls. Sustained contractions elicited by 60 mM KCl were not different among SK3^T/T, SK3^T/T+Dox, and WT mice. However, the rate of onset and magnitude of spontaneously occurring phasic contractions was muted significantly in isolated uterine strips from SK3^T/T mice compared with those from WT mice. These spontaneous contractions were augmented greatly by blockade of SK channels with apamin or by suppression of SK3 expression. Phasic but not tonic contraction in response to oxytocin was depressed in uterine strips from SK3^T/T mice, whereas suppression of SK3 channel expression or treatment with apamin promoted the predominance of large coordinated phasic events over tone. Spontaneous contractions and the phasic component of oxytocin contractions were blocked by nifedipine but not by cyclopiazonic acid. Our findings suggest that SK3 channels play an important role in regulating uterine function by limiting influx through L-type Ca²⁺ channels and disrupting the development of concerted phasic contractile events.

uterus; Ca²⁺-activated K⁺ channel; doxycycline; mouse

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