This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Preterm births account for only 10% of all deliveries, however are associated with over 80% of newborn deaths and more than 95% of major newborn morbidity. Despite efforts toward prevention, there has been a 13% increase in the rate of preterm births over the past decade. The lack of understanding of the mechanism and regulation of uterine contraction has hampered progress towards an effective treatment for preterm labor. Currently used tocolytic agents have little effect in prolonging gestation, suggesting that other methods of preventing preterm labor should be investigated. One potential class of therapeutic targets that has been proposed is K+ channels due to their ability to potently buffer cell excitation. Electrophysiological reports have shown that myometrial cells contain a variety of K+ channel types that may be potential therapeutic targets, including large-conductance Ca2+-activated K+ channels (BKCa channels). BKCa channels play a significant role in uterine contractility. Block of BKCa channels depolarizes myometrial cells and increases contractile activity, while openers induce uterine relaxation. Additionally, these channels are activated by beta-adrenergic agents and other uterine relaxants. A channel similar to the BKCa channel in conductance properties, but lacking its voltage- and Ca2+ - sensitivity, has been described in human myometrium in labor, and may represent the BKCa channel uncoupled from its beta subunit, which mediates Ca2+ - and voltage-sensitivity to this channel. Therefore, one potential aspect of BKCa channel regulation that should be investigated is the role that the recently identified accessory beta subunits may play in modulating the properties and function of these channels during pregnancy. The objective of this proposal is to determine the molecular architetcture of the BKCa channel during parturition and to elucidate the role that K+ channel beta subunits play in regulating uterine activity.
The specific aims are to: 1) determine the expression pattern of the human BKCa channel transcript during parturition; 2) characterize BKCa alpha and beta subunit protein expression in myometrial smooth muscle during parturition; and 3) characterize BKCa channel alpha and beta subunit expression and assembly in human uterine tissue at parturition. These experiments will use molecular and biochemical approaches to define the BKCa channel mechanisms which regulate uterine excitability. The studies will determine the importance of this channel during parturition, and identify the role of this channel as a potential mediator of myometrial membrane repolarization and as a possible target for tocolytic therapy.
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