# Regulatory and Functional Mechanisms in hERG Ion Channels

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $285,065

## Abstract

Human ether á go-go related gene (hERG) potassium channels are of extraordinary clinical importance.
hERG channels play a prominent role in the heart by generating a current that repolarizes cardiac action
potentials. Mutations in the hERG gene and inhibition of hERG channels by the off-target action of prescription
drugs cause a reduction in hERG current that accounts for both inherited and acquired forms of long QT
syndrome (LQTS), a predisposition to cardiac arrhythmias. The disease relevance of hERG emphasizes the
importance of these channels in normal physiological function. hERG channels have highly specialized gating
properties (opening and closing) that optimize them for their cellular roles in the heart and specialized subunit
assembly properties that also control channel gating. hERG (also known as the primary isoform, hERG1a)
associates with another `alpha' subunit isoform, hERG1b. The mechanisms of subunit association are a major
area of interest for understanding how heteromeric hERG1a/hERG1b channels are regulated and gated. The
goal of the proposed experiments is to understand the molecular mechanisms that underlie these
specializations and how they control homomeric hERG1a and heteromeric hERG1a/hERG1b channels. We will
examine hERG1a and hERG1b subunit protein-protein interactions using novel fluorescence methods and
protein biochemistry assays. We will test recent structures of static N- and C-terminal domain interactions
within hERG1a and test how these domain interactions control assembly and dynamically rearrange during
channel gating. 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 engineer small
probes to hERG1a and introduce metal binding sites at locations guided by recent structures and test for
movements with transition metal FRET and voltage. We will also use a functional toolbox of approaches to
examine the structural and functional interactions of hERG1a and hERG1b subunits and the cellular role of
disease-causing mutations in human induced pluripotent stem cell-derived cardiomyocytes, which have a
robust cardiac IKr current formed by hERG1a and hERG1b channel subunits.
 Completion of these studies will lead to a greater understanding of the basic mechanisms for
homomeric hERG1a and heteromeric hERGa1a/hERG1b channel gating, insight into how intracellular domains
of the channels regulate the assembly of hERG1a and hERG1b subunits and how mutations perturb these
interactions. Based on our deep understanding of mechanism, we have developed and will test hERG1a
polypeptides that encode hERG1a functional domains for rescue of hERG1a and hERG1b LQTS mutant
channels. Our outcomes are anticipated to lead to rational biomedical strategies to counteract or enhance the
loss-of-function mutat...

## Key facts

- **NIH application ID:** 10116420
- **Project number:** 5R01GM127523-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MATTHEW C TRUDEAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $285,065
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116420

## Citation

> US National Institutes of Health, RePORTER application 10116420, Regulatory and Functional Mechanisms in hERG Ion Channels (5R01GM127523-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116420. Licensed CC0.

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