# KCNH channel regulation by intracellular ligands

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2020 · $308,558

## Abstract

Ion channels in the KCNH family perform diverse and important physiological functions,
including the regulation of cancer progression, neuronal excitability and cardiac
contraction. KCNH channels contain a Per-Arnt-Sim (PAS) domain in their N-terminal
and cyclic nucleotide-binding homology (CNBH) domain in their C-terminal regions.
These intracellular domains are the key functional domains that are largely responsible
for the distinct properties of KCNH channels that determine their physiological
applications. The goal of this proposal is to identify small molecule ligands that directly
bind to the PAS and CNBH domains and uncover the mechanisms of their action on
KCNH channels. We will identify and functionally characterize KCNH channel ligands
using a novel strategy based on the combination of surface plasmon resonance (SPR)
and electrophysiology as the principal methods. We will first identify small molecule
ligands by screening libraries of small molecules against the PAS and CNBH domains
of KCNH channels with the high-throughput SPR method. We will then determine the
functional effects of the identified small molecule ligands with medium-throughput two-
electrode voltage-clamp method. Finally to uncover molecular mechanisms of action of
the identified ligands we will use a combination of patch-clamp current recordings,
mutagenesis, X-ray crystallography, SPR and structural modeling. These studies will
advance our knowledge of KCNH channel regulation by intracellular ligands and PAS
and CNBH domains, provide pharmacological tools to study physiological contributions
of KCNH channels and will greatly facilitate the development of novel pharmaceutical
agents for treatment of cardiac arrhythmias, cancer and epilepsy.

## Key facts

- **NIH application ID:** 9896844
- **Project number:** 5R01GM124020-03
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Tinatin I Brelidze
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,558
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896844

## Citation

> US National Institutes of Health, RePORTER application 9896844, KCNH channel regulation by intracellular ligands (5R01GM124020-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9896844. Licensed CC0.

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