A successful pregnancy and delivery require two distinct states of uterine activity: a quiescent state characterized by weak, asynchronous, regional contractions throughout pregnancy; and an activated state in which contractions increase in force, frequency, and synchrony to expel the fetus at term. These states are controlled by electrical activity of the uterine (myometrial) smooth muscle cells (MSMCs). Two key ions regulate MSMC electrical activity: calcium (Ca2+), which enters the cell, depolarizes the membrane, and activates the contractile machinery; and potassium (K+), which effluxes from the cell, repolarizes (inside of the membrane more negative than outside) the membrane, and returns the cell to the resting state. The traditional model is that Ca2+ enters through voltage-gated Ca2+ (Cav) channels and activates the large-conductance Ca2+-activated K+ channel KCa1.1. Here, we propose that whereas this model explains the basal, quiescent state, it is insufficient to explain the activated, inflammatory state characteristic of term labor. Instead, we propose a new model in which low KCa1.1 activity and Cav-mediated Ca2+ influx maintain MSMC membrane polarization in basal states, but high KCa1.1 activity and Ca2+ influx through store-operated Ca2+ (SOC) channels are required for membrane repolarization in inflammatory states. This new model is founded on several pieces of published and preliminary data. First, KCa1.1 is substantially more active in MSMCs isolated from laboring women than in those from non-laboring women. Second, when the inflammatory protein alpha-2- macroglobulin (?2M) binds to its receptor, low density lipoprotein receptor-related protein 1 (LRP1), KCa1.1 activity enhances Ca2+ oscillations in MSMCs. Third, these Ca2+ oscillations are not inhibited by the Cav blocker nifedipine, but by SOC inhibitors. Finally, in MSMCs, KCa1.1 interacts with ?2?1, the subunit that traffics Cav to the plasma membrane. To test our model, we will pursue three specific aims: 1) Determine the extent to which KCa1.1 is required for MSMC excitability in basal and inflammatory states; 2) Define the mechanism by which inflammatory stimuli enhance KCa1.1 and Ca2+ channel activity; and 3) Determine the mechanism by which KCa1.1 inhibits Cav-mediated Ca2+ influx. Insights gained from this work may lead to new therapeutic strategies to modulate uterine excitability and prevent aberrant uterine activity.
This proposal tests a novel model about the function of a key ion channel controlling contraction of uterine muscle cells. Information learned from the proposed studies will, in the long term, lead to development of new methods to treat and prevent pregnancy complications such as preterm and post-term labor.
|Lorca, Ramón A; Ma, Xiaofeng; England, Sarah K (2017) The unique N-terminal sequence of the BKCa channel ?-subunit determines its modulation by ?-subunits. PLoS One 12:e0182068|
|Wakle-Prabagaran, Monali; Lorca, Ramón A; Ma, Xiaofeng et al. (2016) BKCa channel regulates calcium oscillations induced by alpha-2-macroglobulin in human myometrial smooth muscle cells. Proc Natl Acad Sci U S A 113:E2335-44|
|Reinl, Erin L; England, Sarah K (2015) Fetal-to-maternal signaling to initiate parturition. J Clin Invest 125:2569-71|
|Rada, Cara C; Pierce, Stephanie L; Grotegut, Chad A et al. (2015) Intrauterine telemetry to measure mouse contractile pressure in vivo. J Vis Exp :e52541|
|Stilley, Julie A W; Christensen, Debora E; Dahlem, Kristin B et al. (2014) FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice. Biol Reprod 91:74|
|Lorca, Ramón A; Prabagaran, Monali; England, Sarah K (2014) Functional insights into modulation of BKCa channel activity to alter myometrial contractility. Front Physiol 5:289|
|Lorca, Ramón A; Stamnes, Susan J; Pillai, Meghan K et al. (2014) N-terminal isoforms of the large-conductance Ca²?-activated K? channel are differentially modulated by the auxiliary ?1-subunit. J Biol Chem 289:10095-103|
|Li, Youe; Lorca, Ramón A; Ma, Xiaofeng et al. (2014) BK channels regulate myometrial contraction by modulating nuclear translocation of NF-?B. Endocrinology 155:3112-22|
|McCloskey, Conor; Rada, Cara; Bailey, Elizabeth et al. (2014) The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy. EMBO Mol Med 6:1161-74|
|Nuno, Daniel W; England, Sarah K; Lamping, Kathryn G (2012) RhoA localization with caveolin-1 regulates vascular contractions to serotonin. Am J Physiol Regul Integr Comp Physiol 303:R959-67|
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