Perilymphatic ATP plays a critical role in modulating cochlear function to protect from loud sound induced hearing loss.

Overview

1. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SE-581 83, Sweden

Abstract

Background: Extracellular adenosine triphosphate (ATP) signalling via purinergic receptors plays a key role in cochlear adaptation to loud sound. Traditionally, ATP activation of purinergic receptor P2X receptors has been proposed to induce a cation shunt, reducing the endolymphatic potential and the driving force for sound transduction. However, direct evidence for this protective mechanism remains limited. Here, we provide direct experimental evidence identifying a distinct, compartment-specific ATP signalling pathway that modulates cochlear function.

Methods: In mature Dunkin–Hartley guinea pigs of either sex, we combined time-resolved confocal microscopy, electrophysiology, live-cell imaging, and fluorescence spectroscopy to characterise how compartmentalised extracellular ATP regulates cochlear function during moderate loud sound exposure.

Findings: ATP delivered to the perilymphatic space where P2X2 receptors localised in Reissner's membrane epithelial cells, supporting cells, and hair cells significantly reduced sound-evoked electrical potentials from 486 μV to 315 μV, outer hair cell stereocilia motion from 135 nm to 99 nm and Hensen's cell motion from 128 nm to 101 nm at 80 dB SPL. These effects were reversible upon ATP removal and accompanied by decreased intracellular calcium. In contrast, ATP applied to the endolymph produced no comparable changes. These findings demonstrate that extracellular ATP in the perilymph protects the cochlea from high-intensity sound through a mechanism distinct from the classical cation shunt model.

Interpretation: These findings reveal a previously unrecognised perilymph-driven ATP signalling pathway that extend beyond the traditional P2X-mediated cation shunt, demonstrating that extracellular ATP plays a critical role in protecting the cochlea mainly from loud sound-induced hearing loss.

Funding: Swedish Research Council 2017-06092 and 2022-00548.

Reproduced under the paper's license (CC BY), from the paper cited above.

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The computer code for data analysis (Matlab) and acquisition (LabView) are available upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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All data are available in the main text or the Supplementary Materials. Source data for figures in the article and Supplementary Figures are available on request from the corresponding author.

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Version 2, 28 September 2026

• Authors: added Sonal Prasad (0000-0002-4455-5097); removed Sonal Prasad

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 4 authors, 6 keywords, 12 MeSH terms, 1 funder, 86 references.

Cite

This paper

Prasad, S., Karlsson, U., Pitkänen, M., & Fridberger, A. (2026). Perilymphatic ATP plays a critical role in modulating cochlear function to protect from loud sound induced hearing loss. EBioMedicine, 130, 106377. https://doi.org/10.1016/j.ebiom.2026.106377

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