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

Nicholas J. Constantino; Caitlin M. Carroll; Holden C. Williams; Hemendra J. Vekaria; Carla M. Yuede; Kai Saito; Patrick W. Sheehan; J. Andy Snipes; Marcus E. Raichle; Erik S. Musiek; Patrick G. Sullivan; Josh M. Morganti; Lance A. Johnson; Shannon L. Macauley

doi:10.1073/pnas.2416578122

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

Nicholas J. Constantino, Caitlin M. Carroll, Holden C. Williams, Hemendra J. Vekaria, Carla M. Yuede, Kai Saito, Patrick W. Sheehan, J. Andy Snipes, Marcus E. Raichle, Erik S. Musiek, Patrick G. Sullivan, Josh M. Morganti, Lance A. Johnson, Shannon L. Macauley

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e2416578122
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	122
Issue number	8
DOIs	https://doi.org/10.1073/pnas.2416578122
State	Published - Feb 25 2025

Bibliographical note

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

Funding

We thank Jamie Hicks for behavior data collection. We thank Erin Sullivan for mitochondrial respiration data collection. We thank Dr. Robert Gould for intellectual discussion. We acknowledge the following grants: K01AG050719 (S.L.M.), R01AG068330 (S.L.M.), BrightFocus Foundation A20201775S (S.L.M.),T32NS115704 (N.J.C.), F31AG066302 (C.C.), R01AG070830 (J.M.M.), R01NS118558 (J.M.M.), R01AG060056 (L.A.J.), R01AG062550 (L.A.J.), R01AG080589 (L.A.J.), and the Alzheimer\u2019s Association (L.A.J.). This research was supported by an Institutional Development Award (IDeA) from the NIGMS and NIH (P30GM127211) and the NIH Center of Biomedical Research Excellence (COBRE) in CNS Metabolism (CNS-Met; P20GM148326). The Washington University Animal Behavior Core is supported in part by funds from the McDonnell Center for Systems Neuroscience, the McDonnell Center for Cellular and Molecular Neuroscience, and the Taylor Family Institute.

Funders	Funder number
Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment
National Institute of General Medical Sciences
Taylor Family Institute
McDonnell Center for Cellular and Molecular Neuroscience
NIH Center of Biomedical Research Excellence
McDonnell Center for Systems Neuroscience
BrightFocus Foundation A20201775S	R01AG062550, R01NS118558, R01AG070830, F31AG066302, R01AG080589, T32NS115704, R01AG060056
CEPR COBRE	P20GM148326
National Institutes of Health (NIH)	P30GM127211
National Institutes of Health (NIH)

Keywords

K channels
arousal
excitability
metabolism
sleep

ASJC Scopus subject areas

General

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10.1073/pnas.2416578122

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Constantino, N. J., Carroll, C. M., Williams, H. C., Vekaria, H. J., Yuede, C. M., Saito, K., Sheehan, P. W., Snipes, J. A., Raichle, M. E., Musiek, E. S., Sullivan, P. G., Morganti, J. M., Johnson, L. A., & Macauley, S. L. (2025). ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep. Proceedings of the National Academy of Sciences of the United States of America, 122(8), Article e2416578122. https://doi.org/10.1073/pnas.2416578122

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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 (KATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking KATP 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-KATP 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.",

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author = "Constantino, \{Nicholas J.\} and Carroll, \{Caitlin M.\} and Williams, \{Holden C.\} and Vekaria, \{Hemendra J.\} and Yuede, \{Carla M.\} and Kai Saito and Sheehan, \{Patrick W.\} and Snipes, \{J. Andy\} and Raichle, \{Marcus E.\} and Musiek, \{Erik S.\} and Sullivan, \{Patrick G.\} and Morganti, \{Josh M.\} and Johnson, \{Lance A.\} and Macauley, \{Shannon L.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the Author(s).",

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Constantino, NJ, Carroll, CM, Williams, HC, Vekaria, HJ, Yuede, CM, Saito, K, Sheehan, PW, Snipes, JA, Raichle, ME, Musiek, ES, Sullivan, PG , Morganti, JM , Johnson, LA & Macauley, SL 2025, 'ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep', Proceedings of the National Academy of Sciences of the United States of America, vol. 122, no. 8, e2416578122. https://doi.org/10.1073/pnas.2416578122

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AU - Constantino, Nicholas J.

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AU - Vekaria, Hemendra J.

AU - Yuede, Carla M.

AU - Saito, Kai

AU - Sheehan, Patrick W.

AU - Snipes, J. Andy

AU - Raichle, Marcus E.

AU - Musiek, Erik S.

AU - Sullivan, Patrick G.

AU - Morganti, Josh M.

AU - Johnson, Lance A.

AU - Macauley, Shannon L.

PY - 2025/2/25

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N2 - 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 (KATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking KATP 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-KATP 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.

AB - 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 (KATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking KATP 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-KATP 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.

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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