# Investigation of the Role of the KCNH Voltage-Gated Potassium Channel Intracellular Domains in Gating

> **NIH NIH K00** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $77,285

## Abstract

PROJECT SUMMARY/ABSTRACT
KCNH channels, also known as the Ether-à-go-go (Eag) family, are voltage-gated potassium ion channels that
have roles in neuronal excitability and cardiac repolarization. The dysfunction of these ion channels is
implicated in a variety of diseases, including cancer, epilepsy, and cardiac arrythmia, making them promising
targets for both diagnostic markers and the development of therapeutic drugs. KCNH channels like EAG and
human Ether-à-go-go–Related Gene (hERG) possess unique and highly conserved intracellular domains that
have evolved to serve unique physiological roles. The N-terminal Per-Arnt-Sim (PAS) domain has diverse
functions in nature: they serve as input modules that mediate protein-protein interactions and as redox
potential, oxygen, and light sensors. The C-terminal cyclic nucleotide binding homology (CNBh) domain has
structural homology to cyclic nucleotide binding (CNB) domains but lack the ability to bind nucleotides. The
intracellular PAS and CNBh domains modulate gating in KCNH channels and are known from structural and
functional studies to associate in a complex. Several disease-associated mutations are concentrated at the
PAS-CNBhD interface, highlighting the physiological importance of their interaction. However, details of how
these domains interact to allosterically regulate critical channel functions, such as slow deactivation in hERG
and calmodulin (CaM) inhibition in EAG1, are not understood. This proposal seeks to investigate the role of the
KCNH channel intracellular domains in gating by combining structural, computational, and electrophysiological
approaches. In Aim 1 (PhD Progress), I describe the presence of a hydrophobic interaction among residues in
the PAS-cap (residues1-25), the downstream globular PAS (residues 26-135), and the CNBh domain of a
neighboring subunit that are critical for slow deactivation in hERG channels. In Aim 2 (F99 Phase), I propose to
uncover the allosteric pathways that mediate Ca2+-CaM inhibition of EAG1 currents. Given the importance of
KCNH channels in various physiological and pathological processes, we expect our novel findings to have
broad implications in neuroscience and beyond.
During the F99 Phase, I will continue my thesis work in my advisor's state-of-the art laboratory with the
guidance and support of my colleagues and graduate trainee peer group. I will learn cutting-edge techniques
and methods of analysis, as well as develop my critical thinking skills to interpret my findings. I will continue
engaging in professional development activities, including journal clubs, seminars, and lab meetings. Finally, I
will share my scientific findings through publications, and oral and poster presentations at scientific meetings.
My long-term goal is to understand the effects of channelopathies within the nervous system. Thus, for the K00
phase, I have identified specific areas, concepts, and techniques I must develop to become a well-rounded
researcher and exper...

## Key facts

- **NIH application ID:** 10899787
- **Project number:** 8K00EY036250-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Whitney Alexandra Stevens-Sostre
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,285
- **Award type:** 8
- **Project period:** 2021-09-01 → 2025-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899787

## Citation

> US National Institutes of Health, RePORTER application 10899787, Investigation of the Role of the KCNH Voltage-Gated Potassium Channel Intracellular Domains in Gating (8K00EY036250-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899787. Licensed CC0.

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