# Conformational Dynamics of hERG Potassium Channels

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $309,000

## Abstract

Human ether á go-go related gene (hERG, KCNH2) potassium channels are of extraordinary clinical
importance because they play a prominent role in heart where they generate a current that repolarizes cardiac
action potentials. Mutations in hERG channels and inhibition by drugs cause a reduction in hERG and account
for inherited and acquired forms of a type of heart disease known as long QT syndrome (LQTS) which
emphasizes the importance of these channels in normal physiological function. The acquired form of LQT is
due to the off-site effects of prescription drugs which inhibit hERG, and are a prevalent and serious clinical
problem. hERG channels have highly specialized gating (opening and closing) properties that optimize them
for their cellular roles in the heart and specialized subunit assembly properties that also control channel gating.
The association of hERG with other regulatory or accessory proteins is also a major area of interest for
understanding how hERG channels are regulated. The goal of the proposed experiments is to understand the
molecular mechanisms that underlie these specializations and how they control hERG current. We will be
testing recent structures showing direct N- and C-terminal domain interactions of hERG that we first showed
using biochemical, electrophysiological and fluorescence measurements, and how these domain interactions
control gating of the channels. Our approach is cutting-edge as we will use electrophysiological recordings to
investigate channel conformational changes and fluorescence microscopy to study how structural interactions
control channel gating and regulation. We will take advantage of non-canonical amino acid biology to introduce
small probes to hERG and introduce metal binding sites at locations guided by structures and probe for
movements with transition metal FRET and voltage. Completion of these studies will lead to a greater
understanding of the basic mechanisms for hERG channel gating and insight into how intracellular domains of
the channel regulate opening and closing. Our outcomes are anticipated to lead to rational biomedical
strategies and new molecular target for the treatment of cardiac arrhythmias.

## Key facts

- **NIH application ID:** 9842553
- **Project number:** 5R01GM130701-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MATTHEW C TRUDEAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,000
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842553

## Citation

> US National Institutes of Health, RePORTER application 9842553, Conformational Dynamics of hERG Potassium Channels (5R01GM130701-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842553. Licensed CC0.

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