# Role of KCNQ2 channels in control of breathing

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2021 · $431,129

## Abstract

SUMMARY
KCNQ channels are key determinants of neuronal activity, and recent clinical evidence identifies
mutations in KCNQ2 as a cause of neonatal epileptic encephalopathy. Most variants
associated with neonatal epileptic encephalopathy are loss-of- function. However, recent work
also identified a recurrent KCNQ2 gain-of-function mutation (R201C) in patients with neonatal-
onset encephalopathy. Patients with both KCNQ2 loss- and gain-of-function mutations exhibit
respiratory dysfunction including central hypoventilation syndrome, a condition thought to result
from loss of respiratory chemoreception, i.e., the mechanism by which the brain regulates
breathing in response to CO2/H+. The retrotrapezoid nucleus (RTN) is an important
chemoreceptor region, and we have shown previously that KCNQ channels regulate basal
activity and neurotransmitter modulation of RTN chemoreceptors. Therefore, we hypothesize
that KCNQ2 channels are the principal KCNQ subunits that control activity of RTN
chemoreceptors. We propose that KNCQ2 gain-of-function will hyperpolarize RTN
chemoreceptors and eliminate their contribution to the drive to breathe, whereas KCNQ2 loss-
of-function mutations will destabilize RTN chemoreceptor activity and disrupt modulation by
neurotransmitters, thus also contributing to unstable breathing. Additionally, we will also test
whether KCNQ2 dysfunction affects not only the RTN but the respiratory control circuit in
general including other chemoreceptors, inspiratory rhythmogenic pre-Bötzinger complex
neurons, and output respiratory motor neurons. Objectives of this study are to investigate, from
the cellular to system level, contributions of KCNQ2 channels to chemoreceptor function and
respiratory control. The two Specific Aims of this project are: 1) determine cellular effects of
KCNQ2 loss- and gain-of-function mutations on respiratory chemoreception, inspiratory rhythm
generation and motor output and 2) determine the essential role of KCNQ2 channels in control
of breathing. The rationale for the proposed research is that by understanding whether and how
KCNQ2 channels regulate neuronal activity across multiple levels of the respiratory circuit, and
respiratory behavior, we will lay a foundation for development of treatments for respiratory
problems like apnea and central hypoventilation syndrome.

## Key facts

- **NIH application ID:** 10085255
- **Project number:** 5R01HL137094-04
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Daniel K Mulkey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,129
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085255

## Citation

> US National Institutes of Health, RePORTER application 10085255, Role of KCNQ2 channels in control of breathing (5R01HL137094-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085255. Licensed CC0.

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