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

Producción científica: Article › revisión exhaustiva

4 Citas (Scopus)

Resumen

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.

Idioma original	English
Número de artículo	e2416578122
Publicación	Proceedings of the National Academy of Sciences of the United States of America
Volumen	122
N.º	8
DOI	https://doi.org/10.1073/pnas.2416578122
Estado	Published - feb 25 2025

Nota bibliográfica

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

Financiación

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’s 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. ACKNOWLEDGMENTS. 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’s 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.

Financiadores	Número del financiador
Alzheimer's Association
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont 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	R01AG062550, R01NS118558, R01AG070830, F31AG066302, T32NS115704, R01AG080589, R01AG060056
CEPR COBRE	P20GM148326
National Institutes of Health (NIH)	P30GM127211

ASJC Scopus subject areas

General

Acceder al documento

10.1073/pnas.2416578122

Otros archivos y enlaces

Citar esto

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), Artículo e2416578122. https://doi.org/10.1073/pnas.2416578122

@article{ba1155255b3242b4868d69d6d6758861,

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",

month = feb,

day = "25",

doi = "10.1073/pnas.2416578122",

language = "English",

volume = "122",

number = "8",

}

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, n.º 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

UR - https://www.scopus.com/pages/publications/85218921129

UR - https://www.scopus.com/pages/publications/85218921129#tab=citedBy

U2 - 10.1073/pnas.2416578122

DO - 10.1073/pnas.2416578122

M3 - Article

C2 - 39964713

AN - SCOPUS:85218921129

SN - 0027-8424

VL - 122

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

Acceder al documento

Otros archivos y enlaces

Huella

Citar esto