# Signaling Mechanisms in Myometrial Cells that Modulate Na+ Leak Channel Non-Selective (NALCN) during Pregnancy and Labor

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2020 · $50,520

## Abstract

ABSTRACT
At the end of pregnancy, the uterus makes a dramatic transition from producing weak, non-synchronous
contractions to producing strong, synchronous contractions capable of delivering the fetus. This transition is
brought about in two ways: 1) the myometrial smooth muscles cells (MSMCs), the muscle cells of the uterus,
become interconnected by gap junctions, and 2) the MSMCs become more sensitive to the action of agonists,
such as the peptide Substance P. However, the mechanisms by which the MSMCs become sensitized to
agonists are not fully understood. This proposal will address this knowledge gap by determining the mechanism
by which the ion channel Sodium Leak Channel Non-Selective (NALCN) is regulated. NALCN is of interest
because NALCN conducts a leak current to depolarize MSMC membranes to the threshold level needed to elicit
an action potential. Additionally, NALCN is required for electrical burst activity and labor efficiency in mice.
Finally, in other cell types, contraction-inducing agonists such as Substance P activate NALCN. The central
hypothesis, which is founded on published and preliminary data, to be tested is that at labor, the auxiliary protein
UNC80 promotes expression of NALCN and localization at the plasma membrane, and sensitizes the channel
to Substance P. Furthermore, Substance P binds to the G protein-coupled receptor Neurokinin Receptor 1 and
activates NALCN via two signaling pathways: SRC kinase and the G proteins Gαq/11. This hypothesis will be
addressed by pursuing two specific aims. Aim 1 will determine the mechanism by which the expression of NALCN
is upregulated and the channel is localized to the plasma membrane and activated at labor. Both heterologous
HEK293 cells and MSMCs and a combination of immunoblot, immunofluorescence, and electrophysiological
techniques will be used to assess the ability of UNC80 to increase expression, membrane localization, and
activity of NALCN. Aim 2 will determine the mechanism by which NALCN becomes sensitized to the action of an
agonist at labor. This aim will be addressed by using HEK293 cells and MSMCs in combination with
pharmacological and electrophysiological approaches. The proposed research is significant because the results
will reveal one mechanism by which MSMCs become sensitized to agonists at labor, providing a foundation on
which to develop therapeutics to dampen or enhance uterine contractility. The proposed studies support a
predoctoral training plan that includes coursework, scientific meetings, consultation with other scientists, and
submitting results for publication in peer-reviewed journals. Overall, this experience and training will prepare the
applicant for a successful career as an academic physician-scientist conducting research relevant to women's
health.

## Key facts

- **NIH application ID:** 9991874
- **Project number:** 5F30HD095591-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Chinwendu Amazu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991874

## Citation

> US National Institutes of Health, RePORTER application 9991874, Signaling Mechanisms in Myometrial Cells that Modulate Na+ Leak Channel Non-Selective (NALCN) during Pregnancy and Labor (5F30HD095591-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991874. Licensed CC0.

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