# Structural Basis for Antiarrhythmic Drug Action

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $743,876

## Abstract

Voltage-gated sodium (Nav1.5) channels initiate action potentials and voltage-gated calcium (Cav1.2) channels
initiate excitation/contraction coupling in cardiac myocytes. They are molecular targets for mutations that cause
arrhythmias and for antiarrhythmic drugs (AADs) used in control and prevention of life-threatening arrhythmias.
We have determined the structures of the bacterial Nav channel NavAb and the model calcium channel CavAb
by X-ray crystallography, and we have determined the structure of the primary cardiac Nav channel Nav1.5 at
high resolution by cryogenic electron microscopy (cryo-EM). This work gave new insight into the structure of the
ion selectivity filter and mechanism of Na and Ca selectivity, the structure of the voltage sensors and mechanisms
of voltage-dependent gating, the activation and inactivation gates and their functional interaction, the receptor
sites for AADs, and the mechanism of access of AADs to their receptor site through the open activation gate and
fenestrations in the sides of the pore. Mutations in Nav1.5 that cause inherited cardiac arrhythmias, including
Dilated Cardiomyopathy and Long QT Syndrome, map onto the pore module, voltage sensor, activation gate,
and fast inactivation gate of Nav and Cav channels, opening the way to probing the pathophysiology of these
mutations at the structural level. Here we will investigate the structural basis for Nav and Cav channel function,
the complex pore-blocking mechanisms of AADs, and the mechanisms underlying the pathophysiological effects
of arrhythmia mutations. Aim 1. We will determine the structure of Nav1.5 channels in resting, open, and
inactivated states and analyze the molecular mechanisms for ion selectivity and conductance in the open state
of Nav1.5. Aim 2. We will prepare complexes of Nav1.5 in the closed, open, and inactivated states with AADs
bound, and we will resolve their structures at high resolution. We will probe structural differences in the drug-
receptor complexes formed by Class IA, IB, and IC AADs in order to understand the structural basis for the
differences in drug action that lead to their different clinical uses. We will examine the role of the fenestrations in
resting-state block by Class IA, IB, and IC AADs. Aim 3. We will insert mutations that cause Dilated
Cardiomyopathy and Long QT Syndrome Type-3 into NavAb and Nav1.5, characterize their pathophysiological
effects on Na currents and gating pore currents, and resolve their structures at high resolution by X-ray
crystallography and/or cryo-EM. Aim 4. We will insert mutations that cause Timothy Syndrome into CavAb and
Cav1.2, determine their pathophysiological effects on Ca and Ba currents, and resolve their structures at high
resolution by X-ray crystallography and cryo-EM. Overall, these studies open the exciting possibility of
understanding cardiac Nav and Cav channels in atomic detail in native and pathogenic conformations and
learning how to manipulate the structures of AADs ...

## Key facts

- **NIH application ID:** 10364048
- **Project number:** 2R01HL112808-10
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** WILLIAM A CATTERALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $743,876
- **Award type:** 2
- **Project period:** 2012-04-06 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364048

## Citation

> US National Institutes of Health, RePORTER application 10364048, Structural Basis for Antiarrhythmic Drug Action (2R01HL112808-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10364048. Licensed CC0.

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