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

Keywords

K channels
arousal
excitability
metabolism
sleep

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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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title = "ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep",

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.",

keywords = "K channels, arousal, excitability, metabolism, sleep",

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).",

year = "2025",

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doi = "10.1073/pnas.2416578122",

language = "English",

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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

TY - JOUR

T1 - ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep

AU - Constantino, Nicholas J.

AU - Carroll, Caitlin M.

AU - Williams, Holden C.

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

Y1 - 2025/2/25

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.

KW - K channels

KW - arousal

KW - excitability

KW - metabolism

KW - sleep

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U2 - 10.1073/pnas.2416578122

DO - 10.1073/pnas.2416578122

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AN - SCOPUS:85218921129

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 8

M1 - e2416578122

ER -

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

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