# Modulation of KCNQ1 channel activity

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $440,956

## Abstract

IKS, the slowly activating delayed rectifier potassium (K+) current in the heart is critical importance to human
physiology as evident from the fact that mutations in either its α (KCNQ1) or β (KCNE1) subunit have been
linked to multiple cardiac arrhythmia syndromes, including long QT syndrome (LQTS); short QT syndrome; and
familial atrial fibrillation. The IKS channel is upregulated during sympathetic stimulation by PKA
phosphorylation, which contributes critically to the physiological shortening of cardiac action potentials in
response to sympathetic nerve activity. This shortening is necessary to ensure adequate ventricular filling time
with accompanying increases in heart rate. It is also during sympathetic stimulation that most sudden deaths
from LQTS occur. Understanding the mechanisms that underlie these mutation-induced arrhythmia syndromes
requires unraveling the molecular interactions between KCNQ1 and KCNE1 within the context of normal and
disease altered IKS channels. But to date, the critical questions of how KCNE1 alters KCNQ1 channel gating
and how IKS channels are modulated by PKA are still not fully answered. Previous studies suggest a possible
interaction between the N-terminus of KCNQ1 and C-terminus of KCNE1 during adrenergic responses. Here,
we will use fluorescent unnatural amino acids as the basis for FRET experiments that will assay the proximity
of these critical intracellular domains with and without adrenergic challenge. Our previous work has revealed
that β-AR regulation of channels requires assembly of a macromolecular complex that includes both KCNQ1
and KCNE1, as well as the adaptor protein Yotiao (AKAP 9). We will here use novel nanobodies to deliver
regulatory domains of PKA directly to the KCNQ1/KCNE1 channel with and without co-assembly with AKAP9.
These experiments will allow dissection of the critical role of AKAP9 in the delivery of signaling molecules to
KCNQ1/KCNE1 from additional putative modulatory roles of the AKAP in modulating channel function post
phosphorylation. In the recent CryoEM structure of KCNQ1 putative interacting residues between KCNQ1 and
KCNE1 map between the VSD and PD, suggesting that KCNE1 is located in this area of the KCNQ1 structure.
We will test whether KCNQ1 and KCNQ1/KCNE1 channels open using different gating hinges in S6. We will
here also identify KCNQ1-KCNE1 interacting residues and determine whether these residues affect the
different gating hinges. PKA has been shown to alter the voltage dependence, sub-conductance occupancy,
and kinetics of IKS channels. Using voltage clamp fluorometry together with mutations and PIP2 depletion that
uncouple the VSD and PD, we will determine whether PKA affect the VSD, PD, and/or VSD-to-PD coupling in
IKS channels. The anticipated results of these experiments will provide a structural basis for control by PKA and
KCNE1 of the physiological function of this critical ion channel and will also provide novel targets for the
development of drugs...

## Key facts

- **NIH application ID:** 9899256
- **Project number:** 5R01GM109762-06
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** ROBERT S KASS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,956
- **Award type:** 5
- **Project period:** 2014-05-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899256

## Citation

> US National Institutes of Health, RePORTER application 9899256, Modulation of KCNQ1 channel activity (5R01GM109762-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899256. Licensed CC0.

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