# A novel molecular mechanism for stimulating uterine contractility by oxytocin

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $522,953

## Abstract

Project Summary
During pregnancy, the uterus gradually transitions from a quiescent state characterized by weak, asynchronous,
regional contractions to an activated state in which contractions increase in force, frequency, and synchrony to
expel the fetus at term. A major driver of this transition is gradual depolarization of the myometrial smooth muscle
cell (MSMC) membrane potential. As the inside of the membrane becomes less negatively charged, the
myometrium becomes more excitable. However, the molecular pathways controlling this transition are unknown,
hampering our ability to develop strategies to regulate uterine contractility to prevent pre- or post-term labor.
Here, we propose to test the central hypothesis that a sodium (Na+) signaling complex formed by the Na+-
activated potassium (K+) channel SLO2.1 and the Na+ leak channel NALCN regulates this transition. This
hypothesis is founded on published and preliminary data we obtained with funding from our previous R01. In
primary human MSMCs isolated at term, we showed that Na+ entry through NALCN activated K+ efflux through
SLO2.1 and hyperpolarized the membrane. Next, we showed that activation of this complex reduced tension in
uterine strips. Finally, we reported that inhibiting this complex induced MSMC depolarization, triggering calcium
(Ca2+) entry through voltage-dependent Ca2+ channels and promoting contractility. Together, these data indicate
that the NALCN/SLO2.1 complex is a strong candidate to control the MSMC membrane potential. However,
because we used human tissues, we could not determine the role of this complex in the gradual depolarization
of the MSMC membrane potential over pregnancy. To address this limitation and fully test our hypothesis, our
objective is to define the function and regulation of the NALCN/SLO2.1 complex across pregnancy in mouse
MSMCs. The goals of this project are to: 1) Define NALCN/SLO2.1 complex activity across pregnancy, 2) Assess
the effects of NALCN/SLO2.1 complex activity on intracellular Ca2+ and uterine contractility and 3) Identify
additional members of the NALCN/SLO2.1 complex in MSMCs and determine their effects on functionality of the
complex. In completing these aims, we will define the main regulators of MSMC membrane potential and how
they change as pregnancy progresses. This work will facilitate future efforts aimed at developing therapeutics to
inhibit the NALCN/SLO2.1 complex to promote labor or to activate the complex to promote quiescence and
prevent preterm labor.

## Key facts

- **NIH application ID:** 10539176
- **Project number:** 2R01HD088097-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sarah K. England
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $522,953
- **Award type:** 2
- **Project period:** 2016-04-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539176

## Citation

> US National Institutes of Health, RePORTER application 10539176, A novel molecular mechanism for stimulating uterine contractility by oxytocin (2R01HD088097-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10539176. Licensed CC0.

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