# Guanidinium Toxins as Molecular Probes for NaV Study

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $436,234

## Abstract

PROJECT SUMMARY
Neuronal excitability relies on the tightly regulated expression and discrete subcellular
localization of voltage-gated sodium ion channels (NaVs). These large membrane protein
complexes control the movement of sodium ions across cell membranes and are responsible for
initiating and propagating action potentials. A desire to better understand the role of NaV
subtypes in electrical signal conduction and the relationship between channel dysregulation and
specific human pathologies (e.g., arrhythmia, epilepsy, skeletal muscle disorders, neuropathic
pain) motivates the development of high precision reagents to facilitate NaV studies.
Investigations of NaV physiology are currently limited by a lack of available methods with which
to modulate the function of individual channel subtypes and to mark changes in cellular
distributions, membrane expression levels, and structural modifications (i.e., protein post-
translational modification) in live cells and in response to external cues.
We are developing small molecule probes for NaV studies based on naturally occurring bis-
guanidinium toxins, among which saxitoxin (STX) is the archetype. These agents function as
molecular ‘corks’ to occlude the extracellular mouth of the ion conductance pore, a desirable
feature for the types of tool compounds we wish to access. De novo chemical synthesis has
enabled the engineering of modified forms of STX, which we will use in combination with protein
mutagenesis and electrophysiology to investigate NaV activity on action potential dynamics.
Understanding how NaV expression is regulated and altered by extrinsic factors—glial cells,
inflammatory mediators, pH, nerve injury—and how such changes modulate action potentials is
a long-term goal of our research. To address these questions, we will develop and validate
three classes of tool compounds. These reagents will enable 1) acute, spatiotemporal inhibition
of individual NaV subtypes; 2) selective fluorescent labeling of membrane NaVs; and 3) affinity
purification of membrane NaVs for proteomics analysis. With the success of our research
program, we will deliver a unique set of high precision chemical probes to help illuminate the
complex physiology of NaVs that underlies bioelectrical signaling.

## Key facts

- **NIH application ID:** 10798153
- **Project number:** 5R01GM117263-08
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Justin Du Bois
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,234
- **Award type:** 5
- **Project period:** 2016-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798153

## Citation

> US National Institutes of Health, RePORTER application 10798153, Guanidinium Toxins as Molecular Probes for NaV Study (5R01GM117263-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10798153. Licensed CC0.

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