The onset and success of labor, at term or preterm, depends on an increase in rhythmic uterine contractions. Contractions can be induced and augmented through oxytocin (OT) treatment, but in recent years, OT has been listed as a High-Alert medication because of its unpredictable outcomes. Therefore, there is a need to better understand its basic mechanisms in regulating uterine contractility. Uterine contractions are regulated by the sum of ion channel activity in myometrial smooth muscle cells (MSMCs). Myometrium possesses an intrinsic ability to produce rhythmic contractions, the pace of which relies on a pacemaker potential. Despite identification of the uterine pacemaker potential in the 1950s, our understanding of the genes and molecular mechanisms that underlie this potential remains limited. In the heart and gastrointestinal tract, pacemaker potentials result from an inward leak of cations through a combination of ion channels. Although a cationic leak current has been measured in the myometrium, the channel that conducts the leak current is unknown. The central hypothesis of this proposal is that a recently described ion channel, the sodium leak channel non-selective (NALCN), in part, underlies the leak current measured in uterine smooth muscle cells, regulates the frequency of uterine contractions, and is modulated by uterotonins including oxytocin and acetylcholine (ACh). This hypothesis is based on preliminary data indicating that NALCN is expressed in the uterus and that knockdown of the gene encoding NALCN reduces the leak current in MSMCs. Additionally, others have shown that NALCN activity can be modulated by agonists, including ACh. This hypothesis will be addressed by pursuing the following aims: 1) determine the extent to which NALCN contributes to the leak current and pacemaker potential in MSMCs and define its regulation throughout pregnancy, 2) determine the effects of uterotonins on leak current activity, and identify the responsible signaling pathway, and 3) elucidate the functional importance of NALCN and the leak current in regulating the pace of spontaneous and agonist-induced uterine contractions.
These aims will be addressed by using both mouse and human uterine tissue with a combination of molecular biology, biochemistry, electrophysiology, pharmacology, RNAi technology, isometric tension recordings, and in vivo intrauterine telemetry. The proposed research is significant because the results will add to our currently vague knowledge of the pacemaker potential and may provide targets for future advancements in the treatment of uterine dysfunction. The proposed studies support a predoctoral training plan that also includes coursework, scientific meetings, and consultation with other scientists. This will prepare the applicant for a successful career in academia. Finally, the end results will be submitted for publication in peer-reviewed journals.

Public Health Relevance

Preterm labor and C-sections are associated with an increased rate of fetal and maternal morbidities, and are associated with hyper- and hypocontractility of the uterus, respectively. The purpose of this study is to determine the contribution of NALCN to the regulation of spontaneous and agonist-induced uterine pacemaking. From these studies we hope to identify a specific gene responsible for modulating the rhythm of uterine contractions, which can be targeted for therapeutic intervention.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F06-T (20)L)
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Ilekis, John V
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Washington University
Obstetrics & Gynecology
Schools of Medicine
Saint Louis
United States
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Reinl, Erin L; Goodwin, Zane A; Raghuraman, Nandini et al. (2017) Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin. Am J Obstet Gynecol 217:214.e1-214.e8
Reinl, Erin L; Cabeza, Rafael; Gregory, Ismail A et al. (2015) Sodium leak channel, non-selective contributes to the leak current in human myometrial smooth muscle cells from pregnant women. Mol Hum Reprod 21:816-24
Reinl, Erin L; England, Sarah K (2015) Fetal-to-maternal signaling to initiate parturition. J Clin Invest 125:2569-71