# A New Approach to Study Mechanically Activated Ion Channels

> **NIH NIH DP2** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $1,305,000

## Abstract

Project summary.
 Some proteins have the unique ability to sense and respond to mechanical force, a process called
mechanotransduction, and can confer mechanosensitivity to cells, tissue, or organelles that express them.
Sound waves in the ear, caress of a feather on the skin, or blood flow in arterial vessels are some instances
where a force-inducing stimulus such as vibration, pressure, or stretch activates mechanically activated (MA) ion
channels that initiate a cascade of events allowing the body to hear, sense touch, or regulate blood pressure. In
the past decade, identification of novel MA ion channels like PIEZOs, K2Ps, TMCs, and OSCA/TMEM63s has
revealed their importance in many physiological processes, but mechanistic details of how these channels sense
force is, strikingly, incomplete. A major challenge impeding the field in comprehending MA channel gating
mechanisms is the lack of a channel activation method that faithfully replicates the transduction of force, within
a physiological environment. This proposal aims to apply photoswitchable lipids as a new and innovative method
to assay mechanically activated (MA) ion channels, which will facilitate the study of these channels with greater
ease, precision, and detail.
 In vivo, mechanical stimulation exerts force, which alters tension within the cell membrane where
mechanosensitive proteins reside. MA ion channels detect this change in membrane tension leading to channel
activation. Traditional in vitro techniques to activate MA channels are rather crude including pushing on
membrane with a blunt glass probe or stretching the membrane by applying pressure. Although these techniques
to alter membrane tension have enabled measurement of MA channel activity, they are indirect, low-throughput,
and poorly mimic physiological stimuli. Here I propose to modulate membrane tension by directly targeting lipids
that encompass the channel using photoswitchable lipids (or photolipids). Incorporation of the photochromic
molecule azobenzene into fatty acyl chains provides optical control over lipids as they undergo cis-trans
isomerization when irradiated with UV-A and blue light. Therefore, azobenzene-modified lipids can be used to
reversibly manipulate membrane structure with light, which can either directly activate or modulate MA ion
channel activity. Using the bona-fide MA ion channel family OSCAs we will screen and optimize photolipids to
selectively change membrane properties on a cellular scale and assay MA channel activity with electrophysiology
and/or calcium imaging. This unique strategy will be combined with structural, functional, and pharmacological
studies to gain a better perspective on the cellular and molecular underpinnings of MA ion channel functions.
Ultimately, this work will also lead to a deeper mechanistic understanding of mechanotransduction processes
that drive vital physiological and pathological states in humans.

## Key facts

- **NIH application ID:** 10242489
- **Project number:** 1DP2GM145302-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Swetha Murthy
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,305,000
- **Award type:** 1
- **Project period:** 2021-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242489

## Citation

> US National Institutes of Health, RePORTER application 10242489, A New Approach to Study Mechanically Activated Ion Channels (1DP2GM145302-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242489. Licensed CC0.

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