# Elucidating the molecular mechanism of ENaC function

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $346,500

## Abstract

Project summary
 The epithelial sodium channel (ENaC) fine-tunes Na+ and water balance and is the
primary regulator of blood pressure and volume through Na+ reabsorption in the distal nephron.
Thus, ENaC is a critical therapeutic target for kidney diseases and blood pressure control. Here
we propose to develop a molecular model for ENaC function by determining high-resolution
structures of ENaC in different functional states. Molecular studies of ENaC have proven difficult
largely because ENaCs are labile, multimeric integral membrane proteins that are activated by
proteolysis of inhibitory domains located in the extracellular domain; how these peptidyl tracts
exert their effects remains unresolved. Our goal is to develop methods for expression and
purification of ENaC in the uncleaved and cleaved conformations. We will apply these methods
to elucidate structure-based mechanisms underpinning ENaC gating, ion permeation, and
allosteric modulation by combining single-particle cryo-electron microscopy and
electrophysiology, together with judiciously chosen biochemical and biophysical assays. The
structures will offer key insight into the molecular basis of proteolytic activation of ENaC
providing positions of the inhibitory domains and identifying critical regions that mediate ENaC
acitivity yielding the first accurate blueprints for rational, structure-based therapeutic strategies.

## Key facts

- **NIH application ID:** 10176541
- **Project number:** 5R01GM138862-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Isabelle Rhyssa Joe Eduria Baconguis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,500
- **Award type:** 5
- **Project period:** 2020-06-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176541

## Citation

> US National Institutes of Health, RePORTER application 10176541, Elucidating the molecular mechanism of ENaC function (5R01GM138862-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10176541. Licensed CC0.

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