Regulation of Uterine Smooth Muscle Excitability

University Of Iowa, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): The molecular mechanisms regulating the transition from uterine quiescence to laboring contractions at parturition are poorly understood. This lack of understanding has impeded progress towards effective treatment for preterm labor. Potassium channels are hypothesized to be potential targets for pharmacological intervention. In myometrial smooth muscle cells (MSMCs), the predominant K+ channel type is the large-conductance Ca2+-activated K+ channel (BKCa channel). Pharmacological block of BKCa channels depolarizes MSMCs and increases contractile activity whereas channel openers relax uterine smooth muscle. This renewal summarizes work my laboratory performed from June 1,1999-September 30, 2003 substantiating that BKCa channel current is attenuated at term pregnancy by: 1) estradiol-sensitive alternative splicing producing isoforms with decreased sensitivity to voltage and Ca2+, 2) channel intemalization, and 3) estrogen-sensitive gestational increases of accessory beta1 subunits. Recent data from our laboratory indicate that novel BKCa channel splice variants are expressed in MSMCs and are subject to post-translational modifications atypical for ion channels. These variants generate novel current phenotypes that may lead to the attenuation in BKCa current, increases in MSMC excitability, and ensuing uterine contraction at late gestation. The objective of this proposal is to determine whether post-translational amidation, current changes produced by novel BKCa channel variants, and silencing of specific BKCa channel isoforms using siRNAs results in increases in uterine contractility. The specific aims of this proposal are to: 1) determine if atypical post-translational modification of the first intracellular loop of the BKCa+132 channel causes a decrease in repolarizing current, 2) characterize the BKCadelta258 isoform and determine whether this isoform decreases MSMC excitability, 3) identity the mechanism by which the BKCadelta162 channel inhibits BKCa channel current and, 4) characterize uterine contractile properties after silencing BKCa channel isoforms using siRNA technology. These studies will aid in determining the physiological role of BKCa channel isoforms in regulating MSMC excitability and uterine contractility and their potential as targets for tocolysis.