Journal article
Sleep pressure accumulates in a voltage-gated lipid peroxidation memory
- Abstract:
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Voltage-gated potassium (KV) channels contain cytoplasmically exposed β-subunits1,2,3,4,5 whose aldo-keto reductase activity6,7,8 is required for the homeostatic regulation of sleep9. Here we show that Hyperkinetic, the β-subunit of the KV1 channel Shaker in Drosophila7, forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetic’s nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls10,11,12,13, such as 4-oxo-2-nonenal or an endogenous analogue generated by illuminating a membrane-bound photosensitizer9,14, abstract an electron pair. NADP+ remains locked in the active site of KVβ until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons15,16,17 use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their KVβ subunits; this biochemical memory influences—and is erased by—spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control16,17 suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 10.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-025-08734-4
Authors
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 084655/Z/08/Z
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V013238/1
- Funder identifier:
- https://ror.org/0472cxd90
- Grant:
- 832467
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 641
- Issue:
- 8061
- Pages:
- 232-239
- Publication date:
- 2025-03-19
- Acceptance date:
- 2025-02-03
- DOI:
- EISSN:
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1476-4687
- ISSN:
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0028-0836
- Pmid:
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40108451
- Language:
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English
- Keywords:
- Pubs id:
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2098109
- Local pid:
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pubs:2098109
- Deposit date:
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2025-03-25
- ARK identifier:
Terms of use
- Copyright holder:
- Rorsman et al.
- Copyright date:
- 2025
- Rights statement:
- Copyright © 2025, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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