# Conformational dynamics of the S4 helix voltage sensor of the potassium channel hERG

> **NIH NIH F32** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $17,141

## Abstract

Project Summary
hERG (human eag-related gene; KCNH2) encodes a voltage activated potassium channel expressed in the
brain and heart. hERG is the delayed-rectifier (IKr) current that drives repolarization in the cells with long action
potentials. Inherited mutations in hERG cause cardiac arrhythmias which can lead to sudden death and
dysregulation of hERG is also associated with schizophrenia. Off target effects of pharmaceuticals inhibit
hERG and this is the primary mechanism for acquired LQT syndrome, a common clinical problem. Despite the
importance of hERG in a myriad of physiological function, how its voltage sensing ability is structurally and
functionally coupled to the mechanisms of ion gating is not well understood. This is predominately due to
limitations in current methods to study the movements of the S4 helix in response to voltage; the key domain in
hERG that senses voltage and transduces the voltage signal to the rest of the channel. To overcome these
limitations new techniques are required to uncover the mechanism of S4 and hERG gating. We hypothesize
that the S4 helix of hERG undergoes large dynamic movements and indirectly regulates channel closing. To
test our hypothesis, we have directly incorporated the small, structurally and functionally non-perturbing,
fluorescent non-canonical amino acid L-ANAP in the S4 helix of hERG with amber codon suppression. We
implement L-ANAP as powerful fluorescent reporter to rigorously probe short-range conformational changes in
hERG channels with transition metal Förster resonance energy transfer (tmFRET). We will measure the
dynamic movements of the S4 helix in hERG channels using simultaneous voltage and spectroscopic
recordings (tmFRET) to measure the distance of S4 helix movement in response to voltage changes. Second,
we will investigate the role of the S4 helix in hERG deactivation(closing) gating by measuring the movement of
the S4 helix with tmFRET in fast deactivating hERG channels compared to wildtype channels, and in
chemically treated slow deactivating channels. Due to the importance of hERG in cardiac excitability and
arrhythmia, determining hERG gating mechanisms directly impacts health and disease.

## Key facts

- **NIH application ID:** 10330951
- **Project number:** 5F32GM134584-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Sara J. Codding
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $17,141
- **Award type:** 5
- **Project period:** 2020-02-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330951

## Citation

> US National Institutes of Health, RePORTER application 10330951, Conformational dynamics of the S4 helix voltage sensor of the potassium channel hERG (5F32GM134584-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10330951. Licensed CC0.

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