ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep
Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (K<sub>ATP</sub>) channels couple glucose-lactate metabolism with excitability. Using mice lacking K<sub>ATP</sub> channel activity (e.g., Kir6.2<sup>-/-</sup> mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2<sup>-/-</sup> mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2<sup>-/-</sup> mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-K<sub>ATP</sub> channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of sleep/wake states and providing the metabolic flexibility to transition between states.
Authors
- Kai Saito
- James A. Snipes
- Carla M. Yuede (ORCID: https://orcid.org/0000-0001-6362-4767)
- Nicholas J. Constantino
- Lance A. Johnson (ORCID: https://orcid.org/0000-0003-0134-7586)
- Erik S. Musiek (ORCID: https://orcid.org/0000-0002-8873-0360)
- Marcus E. Raichle (ORCID: https://orcid.org/0000-0002-1847-9588)
- Holden C. Williams
- Caitlin M. Carroll (ORCID: https://orcid.org/0000-0003-1572-7360)
- Josh M. Morganti (ORCID: https://orcid.org/0000-0002-4183-0049)
- Shannon L. Macauley (ORCID: https://orcid.org/0000-0002-4292-2703)
- Hemendra J. Vekaria (ORCID: https://orcid.org/0000-0001-5945-5235)
- Patrick W. Sheehan (ORCID: https://orcid.org/0000-0001-8476-6246)
- Patrick G. Sullivan (ORCID: https://orcid.org/0000-0001-7418-4760)
Institutions
- University of Kentucky (US)
- Washington University in St. Louis (US)
- University School (US)
- Wake Forest University (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1073/pnas.2416578122
- Citations
- 6
- Primary Topic
- Sleep and Wakefulness Research
- Type
- article
- Field-Weighted Citation Impact
- 7.16
Funders
- Alzheimer's Association
- BrightFocus Foundation
- National Institutes of Health
- McDonnell Center for Systems Neuroscience
- National Institute on Aging
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke