# Potassium channels, membrane potential, and CHD

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $612,216

## Abstract

Project Summary
Congenital heart disease (CHD) leads to severe morbidity and mortality to children in the US and worldwide.
Despite this impact on child health, we simply do not understand the genetic causes of CHD. Recently, trio
based whole exome sequencing has identified a class of voltage-gated potassium channels (multiple KCNH
family members) as candidates for CHD and, specifically heterotaxy, a disorder of left-right (LR) patterning that
has a severe effect on cardiac function. However, a molecular role connecting potassium channels to structural
heart disease and heterotaxy is unprecedented.
 We propose, and our preliminary data support, that KCNH6 defines a new paradigm for cell signaling in
early embryonic cells. Our data support an electrophysiological model where specific germ layers fates
(paraxial mesoderm and ectoderm) are dependent on an ion channel network. Our overarching hypothesis is
that K+ channels define electrical membrane potential and regulate voltage gated Ca2+ channels that establish
an exit from pluripotency towards specific cell fates, gastrulation, and LR patterning providing a plausible
mechanism for our patients with Htx and CHD. Our electrophysiological pathway then integrates with
biochemical signaling pathways that define specific cell fates in the embryo.
 In this proposal revision, we will focus on KCNH6 to see if gene depletion leads to LR patterning defects in
Xenopus. In addition, we will test where in the LR patterning cascade, KCNH6 plays a role. Then, using a
series of judiciously chosen chemical and ionic perturbations, we will test if membrane potential is indeed
essential for pluripotency, cell fate, and calcium regulation. Due to the novelty of this project, we will also
perform unbiased genomics (RNAseq) for discovery of transcriptional targets of  Vm. Finally, we will
measure electrical properties electrophysiologically using both whole-cell voltage clamp and intracellular
recordings and determine the various currents that define membrane potential in early germ cells.
 A major strength of our proposal is our expertise; we have forged a collaboration between Xenopus
developmental biologists and electrophysiologists that will allow us to rigorously investigate membrane
potential as an embryonic patterning mechanism.

## Key facts

- **NIH application ID:** 9996043
- **Project number:** 1R01HL149746-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mustafa K Khokha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $612,216
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996043

## Citation

> US National Institutes of Health, RePORTER application 9996043, Potassium channels, membrane potential, and CHD (1R01HL149746-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996043. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*