KATP Channels Modulate Cortical Activity and Sleep by Regulating Glycolytic Flux

Academic Background

Glucose serves not only as the primary energy source for the brain but also as a biosynthetic substrate for neurotransmitter synthesis. Changes in glycolytic flux can alter neurotransmitter synthesis, thereby modulating cortical electroencephalography (EEG) activity, arousal, and sleep states. ATP-sensitive potassium (KATP) channels act as metabolic sensors that detect intracellular ATP levels to regulate glycolytic flux, arousal, and sleep/wake transitions. However, the specific mechanisms by which KATP channels maintain and transition between sleep/wake states through metabolic regulation remain unclear. This study aims to explore how KATP channels influence cortical activity and sleep/wake states by regulating glycolytic flux and uncover the underlying molecular mechanisms.

Paper Source

This research was conducted by Nicholas J. Constantino, Caitlin M. Carroll, Holden C. Williams, and others from institutions such as the University of Kentucky and Washington University School of Medicine. The paper was published on February 18, 2025, in PNAS (Proceedings of the National Academy of Sciences), titled “ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep.”

Research Workflow and Results

1. Expression Localization of KATP Channels in Neurons

The researchers first analyzed publicly available single-cell RNA sequencing data (brainrnaseq.org and portal.brain-map.org) to determine the primary expression sites of KATP channels. The results showed that the subunits Kir6.2 (encoded by KCNJ11) and SUR1 (encoded by ABCC8) of KATP channels are predominantly expressed in excitatory and inhibitory neurons, particularly in glutamatergic and GABAergic neurons, with minimal expression in non-neuronal cells (e.g., glial cells and vascular cells). This finding suggests that the absence of KATP channels primarily affects neuronal metabolism and excitability.

2. Effects of KATP Channel Deletion on Glycolysis and Neurotransmitter Synthesis

Using oral administration of U-13C-glucose and stable isotope-resolved metabolomics (SIRM), the researchers analyzed glucose metabolism in the brains of KATP channel-deficient mice (Kir6.2−/−) and wild-type mice (WT). The results revealed that glycolytic flux increased while neurotransmitter synthesis decreased in Kir6.2−/− mice. Specifically, pyruvate and lactate levels significantly increased in Kir6.2−/− mice, whereas the synthesis of neurotransmitter precursors such as glutamine and GABA decreased. This indicates that the absence of KATP channels directs glucose toward glycolysis rather than neurotransmitter biosynthesis.

3. Impact of KATP Channel Deletion on Mitochondrial Respiration

To rule out potential effects of mitochondrial dysfunction on increased glycolytic flux, the researchers isolated synaptic and nonsynaptic mitochondria from Kir6.2−/− and WT mice and measured their oxygen consumption rates (OCR). The results showed no significant differences in mitochondrial respiration between the two groups, indicating that the increase in glycolytic flux was directly caused by KATP channel deletion rather than mitochondrial dysfunction.

4. Effects of KATP Channel Deletion on EEG Activity and Behavior

Through EEG recordings, the researchers found that absolute EEG power significantly decreased across all sleep/wake states in Kir6.2−/− mice, particularly in the θ (4–8 Hz) and α (8–13 Hz) frequency bands associated with arousal. Additionally, Kir6.2−/− mice exhibited delayed induction and emergence times during anesthesia, suggesting impaired wake-to-sleep transitions. Behavioral experiments further revealed reduced anxiety-like behaviors in Kir6.2−/− mice but a decline in memory function.

5. Effects of KATP Channel Deletion on Sleep/Wake States

Using EEG/electromyography (EMG) recordings, the researchers observed that Kir6.2−/− mice spent significantly more time awake at the onset of the light period (ZT0–3), indicating delayed transitions from wakefulness to sleep. Furthermore, relative EEG power shifted from low frequencies (e.g., θ waves) to high frequencies (e.g., γ waves) during sleep in Kir6.2−/− mice, suggesting reduced sleep quality.

6. Effects of KATP Channel Deletion on Interstitial Fluid (ISF) Lactate Dynamics

By simultaneously recording EEG/EMG and ISF lactate levels, the researchers found that changes in ISF lactate were significantly slower during sleep/wake transitions in Kir6.2−/− mice. Specifically, ISF lactate increased more slowly during transitions from sleep to wakefulness and decreased more slowly during transitions from wakefulness to sleep in Kir6.2−/− mice. This demonstrates that KATP channels play a critical role in regulating ISF lactate dynamics, thereby influencing sleep/wake transitions.

7. Circadian Rhythmic Expression of KATP Channels

Through RNA sequencing and rhythmicity analysis, the researchers discovered that the expression of KCNJ11 and ABCC8 genes exhibits circadian rhythmicity, peaking during the light period and decreasing during the dark period. This finding indicates that KATP channel expression is regulated by circadian rhythms, potentially explaining why sleep/wake state changes are more pronounced in Kir6.2−/− mice during specific time periods.

Conclusions and Significance

This study reveals how KATP channels regulate glycolytic flux to influence cortical activity, arousal, and sleep/wake states. Specifically, KATP channel deletion directs glucose toward glycolysis rather than neurotransmitter synthesis, thereby reducing cortical EEG activity and delaying sleep/wake transitions. Moreover, the circadian regulation of KATP channel expression further influences the maintenance and transition of sleep/wake states. This research deepens our understanding of the relationship between metabolism and neural activity and provides new perspectives for studying diseases related to KATP channel dysfunction (e.g., type 2 diabetes, DEND syndrome).

Research Highlights

1. Metabolic Regulation by KATP Channels: The study is the first to reveal how KATP channels influence neurotransmitter synthesis and cortical activity by regulating glycolytic flux.
2. Molecular Mechanisms of Sleep/Wake Transitions: It elucidates the critical role of KATP channels in regulating ISF lactate dynamics and sleep/wake transitions.
3. Interaction Between Circadian Rhythms and Metabolism: The discovery of circadian regulation of KATP channel expression provides new insights into the diurnal variations of sleep/wake states.

This study offers novel insights into the complex relationship between metabolism and neural activity and identifies potential therapeutic targets for related disorders.