# Molecular Identity and Physiological Function of Novel Chloride Channels

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $199,747

## Abstract

PROJECT SUMMARY/ABSTRACT (R35 GM124824)
Chloride is the most abundant free anion in animal cells. Chloride channels play a wide range of functions
including cell volume regulation, fluid secretion, regulation of excitability, and acidification of intracellular
organelles. Their physiological role is impressively illustrated by many genetic diseases involving chloride
dysregulation, such as cystic fibrosis, myotonia, and epilepsy. However, despite recent progress, chloride
channels have long suffered as poor cousins in the aristocratic family of ion channels. For decades, the field has
been dominated by sodium, potassium and calcium channels. Indeed, there are still many electrophysiologically
well-characterized chloride channels without molecular identity. This gap makes it impossible to elucidate their
precise function and how their dysfunction leads to disease. In the previous R35 MIRA ESI funding period, we
performed an unbiased RNAi screen and identified PAC, a novel membrane protein with no sequence similarity
to other ion channels, as the long sought-after acid or proton-activated chloride (PAC) channel. By mediating
chloride influx and subsequent cell swelling, PAC currents have been implicated in acid-induced cell injury. We
generated PAC knockout mice and demonstrated that PAC plays a key role in acid-induced cell death in vitro
and ischemic brain injury in vivo. Thus, PAC is a potential drug target for stroke and other acidosis-associated
diseases. By combining mutagenesis, patch-clamp recording, and cryo-EM, we revealed for the first time the
trimeric assembly, ion conducting pathway, the basis of anion selectivity, pH-dependent conformational change,
and pH-sensing mechanism of this new channel. Discovery of a novel channel represents a breakthrough that
opens up a new field. In the next 5 years, we will focus on the diverse regulatory mechanisms of the PAC channel
and its surprising physiological function in vesicular acidification that we have recently discovered. The long-term
goal of this MIRA program is to apply a multi-disciplinary approach including high-throughput functional
genomics, patch-clamp electrophysiology, structural biology, imaging, and mouse genetics to the underexplored
area of chloride channel biology.

## Key facts

- **NIH application ID:** 11033074
- **Project number:** 3R35GM124824-07S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Zhaozhu Qiu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $199,747
- **Award type:** 3
- **Project period:** 2017-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11033074

## Citation

> US National Institutes of Health, RePORTER application 11033074, Molecular Identity and Physiological Function of Novel Chloride Channels (3R35GM124824-07S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11033074. Licensed CC0.

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