# Development of Small-molecule Potentiators of Kir4.1/5.1 Potassium Channels

> **NIH NIH F32** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $19,883

## Abstract

PROJECT SUMMARY/ABSTRACT
Heterotetrameric inward rectifier potassium (Kir) channels composed of Kir4.1 (KCNJ10) and Kir5.1 (KCNJ16)
play key roles in regulation of sodium, potassium, and water balance by the distal convoluted tubule (DCT) of
the renal tubule. Loss-of- function mutations in KCNJ10 lead to EAST syndrome, which is characterized by
neurological dysfunction (e.g. epilepsy, ataxia, and sensorineural deafness) and renal salt wasting. While genetic
approaches have been invaluable for understanding the physiology of renal Kir4.1/5.1, the pharmacological tools
for probing the therapeutic potential of these channels have been limited to non-specific inhibitors. As part of a
NIDDK-funded high-throughput screening program aimed at developing potent and specific Kir4.1/5.1 small-
molecule modulators, we have recently discovered the first known potentiators/activators of Kir4.1/5.1. The major
focus of my F32 fellowship will be to optimize the potency and selectivity of one of these potentiators, termed
VU206, to understand its molecular mechanism of action and test its ability to rescue the function of select EAST
mutant channels. In Aim 1, medicinal chemistry will be employed to create iterative analog libraries of VU206 to
evaluate the relationship between changes on the functional groups of the chemical scaffold and potency and
selectivity toward Kir4.1/5.1. An established quantitative thallium flux assay will be used to screen VU206 and
analog libraries against Kir4.1/5.1 and ten different Kir channels. Potentiators with the greatest potency and
selectivity will be confirmed using “gold standard” manual patch clamp electrophysiology. Finally, VU206 and/or
optimized potentiators will be tested against native rat distal convoluted tubule Kir4.1/5.1 channels as a step
towards developing an in vivo-active channel potentiator. In Aim 2, we will determine the molecular mechanism
of action of VU206. I will use single channel analysis to test the hypothesis that VU206 potentiates Kir4.1/5.1
activity via increased open-state probability (Po), as opposed to increased unitary conductance. Effects of VU206
on Po would be consistent with opening of the helix-bundle crossing (HBC) gate, a well-established mechanism
for regulating the channel by changes in intracellular pH. Next, we will systematically evaluate the sensitivity of
EAST gating mutations, R65P, A167V, and R175Q, to changes in intracellular pH and VU206 to determine
whether channel dysfunction occurs via a conserved molecular mechanism. Successful completion of these
Aims will lead to the development of first-in-class potentiators of Kir4.1/5.1, provide important new insights into
how Kir4.1/5.1 channels can be opened pharmacologically, and contribute to a growing “toolkit” for evaluating
the integrative physiology and therapeutic potential of Kir4.1/5.1 channels in the regulation of renal tubule
function. Importantly, this fellowship experience will prepare me for a successful career as an i...

## Key facts

- **NIH application ID:** 10426116
- **Project number:** 5F32DK127679-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Samantha McClenahan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $19,883
- **Award type:** 5
- **Project period:** 2021-05-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426116

## Citation

> US National Institutes of Health, RePORTER application 10426116, Development of Small-molecule Potentiators of Kir4.1/5.1 Potassium Channels (5F32DK127679-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10426116. Licensed CC0.

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