# Elucidating the Role of KCNJ6 in a Human Neuronal Model of Alcohol Use Disorder

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $43,920

## Abstract

Project Summary
 Alcohol Use Disorders (AUDs) are highly prevalent among adults and adolescents worldwide, and pose
a significant public health problem. Furthermore, they are highly heritable, and remain largely untreated. This
project aims to identify cellular and molecular mechanisms underlying AUD development through the
investigation of KCNJ6 upregulation in human neurons. Multiple single nucleotide polymorphisms (SNPs) in
KCNJ6 have a genome wide association with an AUD risk electroencephalogram endophenotype. Specifically,
SNPs associated with a reduction in frontal theta event-related oscillations in measures of attention and
inhibitory control are also associated with an upregulation of KCNJ6 mRNA in the frontal cortex. KCNJ6
encodes the G protein-activated inwardly rectifying potassium channel 2 (GIRK2), a protein contributing to the
maintenance of inhibitory tone in the brain. Therefore, the first aim is to elucidate functional effects of
upregulated KCNJ6 expression in neurons derived from control human induced pluripotent stem cells. This
approach capitalizes on the translational potential of hiPSC-derived neurons and minimizes the confounds of
inter-individual variability by comparing endogenous and elevated KCNJ6 expression in neurons with the same
genetic background. Calcium imaging and patch clamp electrophysiology will be used to measure changes in
neuronal activity associated with elevated GIRK2, such as decreased spontaneous activity and excitability. The
second aim is to test the effects of acute and chronic ethanol exposure on these neural cultures using calcium
imaging and RNA sequencing analyses of differential gene expression. Alcohol directly activates GIRK2
channels, and elevated levels of the protein could result in increased neuronal inhibition in response to alcohol
exposure. Furthermore, exposure to alcohol and changes in neuronal activity may impact global gene
expression as measured by RNAseq, supporting the hypothesis that elevated KCNJ6 impacts transcriptomic
adaptations to alcohol treatment. Overall, this project provides a multifaceted characterization of human
neurons in an etiologically-relevant model of alcohol use disorder, potentially identifying mechanisms suitable
for therapeutic targeting.

## Key facts

- **NIH application ID:** 10019308
- **Project number:** 5F31AA027949-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Iya Prytkova
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,920
- **Award type:** 5
- **Project period:** 2019-08-14 → 2022-09-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019308

## Citation

> US National Institutes of Health, RePORTER application 10019308, Elucidating the Role of KCNJ6 in a Human Neuronal Model of Alcohol Use Disorder (5F31AA027949-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10019308. Licensed CC0.

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