# Calcium modification of voltage gated sodium channels

> **NIH NIH R35** · MISSISSIPPI STATE UNIVERSITY · 2022 · $363,750

## Abstract

PROJECT SUMMARY
Voltage-gated sodium channels (NaVs) are essential for action potentials in excitable cells located throughout
the body (central nervous system, smooth muscle, heart and skeletal muscle). Loss of, improper, or untimely
function, can each cause or contribute to disease. Many individual point mutations in the genes of NaV or
accessory proteins have been associated with disease; some of which can be life threatening. Many disease
associated mutations are located at or are near NaV accessory protein binding sites; therefore significant effort
has been put forth by many investigators to characterize the mechanisms that underlie ion channel gating
modification and in physiology and disease.
 It is well established that Ca2+ alters NaV function, and the Ca2+ sensing protein Calmodulin (CaM) has
a prominent role in this process. Structural investigations have identified several distinct CaM-NaV interactions.
However, the posited physiological function and interpretation of data are controversial. Early studies relied on
measuring NaV function in the absence or presence of Ca2+ and generated seemingly disparate results.
Subsequent investigation revealed the mechanism(s) of Ca2+driven NaV modification are complex and involve
multiple accessory proteins, thereby rendering much of the data ambiguous.
 Recently, I identified a high-affinity interaction between CaM and part of NaV that is directly responsible
for inactivating NaV conduction. I was able to utilize my in-depth structural characterization to impair the
interaction without conferring additional modification to NaV function. This is a notable accomplishment given
this part of the channel undergoes rapid conformational change during each functional cycle. Because of this, I
could for the first time clearly attribute modified NaV function to reduced CaM binding. My data demonstrate
that channels with this reduced CaM interaction require longer to recover from the inactivated state.
 Considering my structure / function findings with available literature suggest a paradigm of CaM
Facilitated Recovery from Inactivation (CFRI). As demonstrated in my recent papers and preliminary data, CaM
engages several NaV isoforms with high affinity, suggesting a universal model of regulation. My findings are in
direct conflict with other reports that posit models of CaM Dependent Inactivation (CDI) and [Ca2+] insensitivity.
These opposing models arise from knowledge gaps regarding (i) the kinetic rates of CaM interactions and (ii)
the precise role of each CaM interaction in an excitable cell that contains oscillating [Ca2+].
 My proposal addresses these knowledge gaps by uniquely combining structural biology, stopped-flow
kinetics, and electrophysiology to dissect the roles of the CaM-NaV interactions in excitable cells. I will then
explore if I can alter the kinetics of specific interactions by engineering a small molecule probe. This work will
test CFRI (physiology and disease), as well as explore n...

## Key facts

- **NIH application ID:** 10447183
- **Project number:** 5R35GM142868-02
- **Recipient organization:** MISSISSIPPI STATE UNIVERSITY
- **Principal Investigator:** Christopher N. Johnson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,750
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447183

## Citation

> US National Institutes of Health, RePORTER application 10447183, Calcium modification of voltage gated sodium channels (5R35GM142868-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10447183. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*