# The role of lipid raft disruption in the activation of TREK-1 channels by anesthetics

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $427,478

## Abstract

PROJECT SUMMARY
The molecular mechanism of inhaled anesthetics in general anesthesia remains an important unanswered
question in neuroscience and human health. Since the first demonstration of ether-induced anesthesia more
than 160 years ago, theories of anesthesia have sought to understand the role of the membrane in anesthetic
action. This application seeks to establishes the plasma membrane as a relevant target for inhaled
anesthetics. Lipid membranes spontaneously partition into regions of ordered and discorded lipids known as
lipid rafts. Palmitoylation of proteins drives the proteins into the ordered phase. We have shown that
anesthetics disrupt these domains in live cell membranes, but disruption has not been linked to anesthetic
ion channels.
We will test the hypothesis that anesthetics disruption of lipid rafts releases lipid modifying enzymes to activate
potassium channels through a chemical signal. Specifically, GM1 rafts sequester phospholipase D (PLD),
disruption of the raft releases PLD allowing the enzyme to find its substrate and generate anionic lipid
phosphatidic acid (PA). The PA then regulates the two-pore domain potassium channel (K2P) TREK-1. TREK-
1 is also an anesthetic sensitive channel. We aim to characterize the effects of anesthetics on lipid raft
structure in the membrane. In a second aim, we will elucidate the mechanism of TREK-1 activation through
anesthetic disruption of the membrane and in so doing establish the membrane as a bon a fide target of
anesthetic action. In a third aim we will develop better imaging tools and a live cell fluorescent assay for
monitoring raft disruption in cells.

## Key facts

- **NIH application ID:** 10595454
- **Project number:** 6R01NS112534-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Scott B Hansen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $427,478
- **Award type:** 6
- **Project period:** 2019-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595454

## Citation

> US National Institutes of Health, RePORTER application 10595454, The role of lipid raft disruption in the activation of TREK-1 channels by anesthetics (6R01NS112534-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10595454. Licensed CC0.

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