A NOVEL MOLECULAR MECHANISM FOR STIMULATING UTERINE CONTRACTILITY BY OXYTOCIN

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 DESCRIPTION (provided by applicant): Proper timing of delivery is important to the immediate and life-long health of both the newborn and the mother, but this event is often mistimed; in the U.S., approximately 12% of babies are born prematurely and up to 10% of pregnancies are described as post-term. For most of pregnancy, the uterus is maintained in a quiescent, non-contractile state in which the myometrial smooth muscle cells (MSMCs) are hyperpolarized, non-excitable, and quiescent. At term, the MSMCs become depolarized, excitable, and contractile. Currently, our limited understanding of how this transition is controlld hampers our ability to treat dysfunctional labor. Numerous ion channels are expressed in the MSMCs and contribute to regulation of uterine excitability. In particular, K+ channels play an important role in maintaining quiescence by controlling MSMC membrane potential by hyperpolarizing the membrane. Another key regulator in control of MSMC excitability is the hormone oxytocin, which binds to the oxytocin receptor (OTR), a Gαq-coupled G-protein coupled receptor (GαqCR). As a result, Protein Kinase C (PKC) is activated and Ca2+ is released from intracellular stores, causing activation of actomyosin contraction. Additionally, it has been proposed that oxytocin triggers Ca2+ influx through voltage-dependent calcium channels by depolarizing the MSMC plasma membrane. However, the molecular mechanism responsible for this depolarization has not been established. Here, we propose to test the central hypothesis that the sodium-activated K+ channel SLO2.1 plays a key role in controlling the resting membrane potential of MSMCs and that its activity is down-regulated at term by either oxytocin-mediated inhibition or decreased expression, resulting in membrane depolarization. Several lines of evidence support this hypothesis. First, our preliminary data indicate that SLO2.1 is expressed in human MSMCs. Second, we report that SLO2.1 activity is modulated by oxytocin in both heterologous systems and MSMCs. Finally, SLO2.1 is known to be regulated by GαqCRs. The goals of this projects are the 1) define the temporal and spatial distribution of SLO2.1 channels in MSMCs, 2) investigate modulation of SLO2.1 channels by oxytocin; and 3) assess the contribution of SLO2.1 channels to regulation of uterine contractility. The research proposed here will establish the molecular pathways that regulate SLO2.1 activity, providing a biological basis for therapies designed to modulate uterine excitability.