# The molecular architecture and mechanism of the Proton Activated Chloride (PAC) Channel.

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $144

## Abstract

Project Summary
 Ischemic strokes can cause long-term cognitive damage, leading to reduced mobility in nearly half of
stroke survivors. Brain tissue damage that occurs during and preceding an ischemic event is often largely in part
due to severe local tissue acidosis. While the molecular mechanism of how acidosis leads to tissue damage is
largely unknown, proton-gated ion channels are thought to play a role. A novel proton-gated chloride channel
has been recently identified as the previously uncharacterized gene, TMEM206, now commonly referred to as
the Proton-Activated Chloride (PAC) Channel. While recent studies have implicated PAC in acid-induced cell
death, there exists no molecular justification of the channel’s proton-activated chloride currents. This proposal
will integrate electrophysiological, biochemical, and high-resolution structural experiments to elucidate the
structure-based mechanisms that govern the function of PAC. In support of this goal, I will first obtain the high-
resolution structures of PAC’s resting and active functional state using single particle cryo-electron microscopy
(Cryo-EM). These structures will provide fundamental insights into the architecture, stoichiometry, and unique
protein folding of PAC. This information will also expand our knowledge surrounding the physical and chemical
properties of proton-gated ion channels, as well as broadly inform the structure/function relationship of ion
channels. I will then ascertain the molecular underpinnings of PAC’s pH-dependent mechanism and pore
properties by probing PAC’s function using structure-directed mutagenesis and electrophysiological
experiments. These experiments will establish a link between the molecular architecture and physiology of PAC.
Ultimately, this proposal will define structure-based, biochemical mechanisms for PAC’s function, which will lay
the foundation for future studies and may inform the development of therapeutic agents to mitigate neuronal
damage in ischemic events.
 As a neuroscience graduate student whose goal is to become an independent academic scientist that
will study the structure/function of ligand-gated ion channels of the nervous system, this project will directly
expand my knowledge base and technical skillset in ion channels, membrane protein biochemistry,
electrophysiology, and cryo-EM. The study into the molecular architecture and mechanism of PAC will be
pursued under the mentorship of Dr. Eric Gouaux, an expert in ligand-gated ion channels and leader in
membrane protein structural biology. Dr. Gouaux is a senior scientist at the Vollum Institute at OHSU, an
electrophysiology powerhouse that is home to one of three national centers for Cryo-EM, Pacific Northwest
Center for Cryo-EM (PNCC). Taken together, the project will not only illuminate critical insights into a novel
proton-activated channel, but will also provide me with the necessary knowledge, biophysical tool-kit, and
professional skills I need to achieve my long-term ...

## Key facts

- **NIH application ID:** 10311483
- **Project number:** 5F31NS120713-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Makayla Freitas
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $144
- **Award type:** 5
- **Project period:** 2020-09-28 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311483

## Citation

> US National Institutes of Health, RePORTER application 10311483, The molecular architecture and mechanism of the Proton Activated Chloride (PAC) Channel. (5F31NS120713-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10311483. Licensed CC0.

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