ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep

Authors

• Nicholas J. Constantino, University of Kentucky College of MedicineFollow
• Caitlin M. Carroll, Wake Forest School of Medicine
• Holden C. Williams, University of Kentucky College of MedicineFollow
• Hemendra J. Vekaria, University of Kentucky College of MedicineFollow
• Carla M. Yuede, Washington University School of Medicine in St. Louis
• Kai Saito, University of Kentucky College of Medicine
• Patrick W. Sheehan, Washington University School of Medicine in St. Louis
• J. Andy Snipes, University of Kentucky College of Medicine
• Marcus E. Raichle, Washington University School of Medicine in St. LouisFollow
• Erik S. Musiek, Washington University School of Medicine in St. Louis
• Patrick G. Sullivan, University of KentuckyFollow
• Josh M. Morganti, University of KentuckyFollow
• Lance A. Johnson, University of KentuckyFollow
• Shannon L. Macauley, University of KentuckyFollow

Abstract

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_ATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking K_ATP channel activity (e.g., Kir6.2^−/− mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2^−/− mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2^−/− 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_ATP 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.

Document Type

Article

Publication Date

2-25-2025

Notes/Citation Information

Publisher Copyright: Copyright © 2025 the Author(s).

Digital Object Identifier (DOI)

10.1073/pnas.2416578122

Archival?

Archival

Repository Citation

Constantino, Nicholas J.; Carroll, Caitlin M.; Williams, Holden C.; Vekaria, Hemendra J.; Yuede, Carla M.; Saito, Kai; Sheehan, Patrick W.; Snipes, J. Andy; Raichle, Marcus E.; Musiek, Erik S.; Sullivan, Patrick G.; Morganti, Josh M.; Johnson, Lance A.; and Macauley, Shannon L., "ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep" (2025). Physiology Faculty Publications. 262.
https://uknowledge.uky.edu/physiology_facpub/262