# Structural and mechanistic basis of cellular volume control

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $69,306

## Abstract

Project Summary
Volume control is critical for cellular responses to osmotic stress and for modulating cell
size during growth, migration, and death. Osmotic forces dictate that a cell exposed to a
hypotonic solution will swell and even burst, a property routinely used for cell lysis.
However, researchers noted in the 1980's that many vertebrate cell types respond to
swelling by releasing chloride ions. This generates an observable current, corrects the
osmotic imbalance, and leads to cell shrinking. The hypothetical channel mediating this
apparently ubiquitous activity was termed the “volume-regulated anion channel” or
VRAC. In addition to controlling cell volume, VRAC is implicated in membrane passage
of physiologically and medically important molecules, such as the neurotransmitter
glutamate and the anti-cancer drug Cisplatin. Recently, the molecular identity of VRAC
activity has been determined to be heteromeric complexes of LRRC8 proteins. This
knowledge opens up multiple questions about VRAC function, including precisely how
the channel is composed, how these channels sense osmotic changes, how they are
gated, and which features of the VRAC pore determine anion selectivity and passage of
diverse small molecules. This project addresses these questions using a combined
structural and electrophysiological approach. The specific aims of the study are: (1) To
express and purify defined LRRC8 complexes; (2) to determine the structure of LRRC8
channels; and (3) to conduct in vivo and in vitro electrophysiological experiments on
channels to determine the mechanism for their function and regulation. Completion of
these aims will reveal the architecture of a novel cellular gateway and provide a
molecular mechanism for cellular volume control.

## Key facts

- **NIH application ID:** 9860916
- **Project number:** 5F32GM128263-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** David Matthew Kern
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2019-01-05 → 2021-01-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860916

## Citation

> US National Institutes of Health, RePORTER application 9860916, Structural and mechanistic basis of cellular volume control (5F32GM128263-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9860916. Licensed CC0.

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