# Regulation and dysregulation of sodium channels by by calmodulin

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $492,931

## Abstract

Project Summary
Sudden cardiac death is a leading cause of mortality in the United States and often results from cardiac
arrhythmias. Mutations in Na+ channels, particularly in their carboxy terminal domains (CTDs), dysregulate beat-
to-beat cycling of Na+ and Ca2+, and thereby, precipitate arrhythmias. Similarly, mutations in calmodulin (CaM),
which closely regulates these channels, are also linked to arrhythmias. However, the role of Na+ channels in
arrhythmogenesis remains unclear. NavCTD mutations, which alter the affinity of Nav CaM, impair fast
inactivation and induce proarrhythmic late Nav current (INa). This particularly is evident for Nav isoforms which
exhibits the lowest CaM affinity and correspondingly, the largest of late INa magnitude relative to peak INa. Our
recent studies indicate an important role for these Nav isoforms in late INa-mediated arrhythmias. However, the
arrhythmogenic impact of Nav dysregulation in calmodulin-driven arrhythmias remains unclear. Based on strong
preliminary data from our laboratory, we hypothesize that affinity of CaM for Nav will dictate the magnitude of
arrhythmogenic late INa. Diminished CaM binding to the NavCTD will increase late INa, while enhanced binding
will hasten channel inactivation, mitigating proarrhythmic late INa. Thus, we propose to: 1) Assess the extent and
mechanism of NaV dysregulation by CaM. 2) Elucidate the relative contribution of mutant CaM-mediated Nav
dysfunction to calmodulinopathy associated arrhythmias. 3) Examine the antiarrhythmic potential of enhancing
CaM-Nav interaction. Thus, by understanding calmodulinopathies, we aim to discover approaches to prevent
arrhythmias stemming from both aberrant CaM-NaV interaction and abnormal NaV function.

## Key facts

- **NIH application ID:** 10211340
- **Project number:** 1R01HL155378-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Przemyslaw Radwanski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $492,931
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211340

## Citation

> US National Institutes of Health, RePORTER application 10211340, Regulation and dysregulation of sodium channels by by calmodulin (1R01HL155378-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10211340. Licensed CC0.

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