The Na+/K+ pump dominates control of glycolysis in hippocampal dentate granule cells
- Harvard Medical School, United States
Abstract
Cellular ATP that is consumed to perform energetically expensive tasks must be replenished by new ATP through the activation of metabolism. Neuronal stimulation, an energetically demanding process, transiently activates aerobic glycolysis, but the precise mechanism underlying this glycolysis activation has not been determined. We previously showed that neuronal glycolysis is correlated with Ca2+ influx, but is not activated by feedforward Ca2+ signaling (Díaz-García, Meyer, et al., 2021). Since ATP-powered Na+ and Ca2+ pumping activities are increased following stimulation to restore ion gradients and are estimated to consume most neuronal ATP, we aimed to determine if they are coupled to neuronal glycolysis activation. By using two-photon imaging of fluorescent biosensors and dyes in dentate granule cell somas of acute mouse hippocampal slices, we observed that production of cytoplasmic NADH, a byproduct of glycolysis, is strongly coupled to changes in intracellular Na+, while intracellular Ca2+ could only increase NADH production if both forward Na+/Ca2+ exchange and Na+/K+ pump activity were intact. Additionally, antidromic stimulation-induced intracellular [Na+] increases were reduced >50% by blocking Ca2+ entry. These results indicate that neuronal glycolysis activation is predominantly a response to an increase in activity of the Na+/K+ pump, which is strongly potentiated by Na+ influx through the Na+/Ca2+ exchanger during extrusion of Ca2+ following stimulation.
Data availability
All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Carlos Manlio Díaz-García
Funding
National Institute of Neurological Disorders and Stroke (R01 NS102586)
- Gary Yellen
National Institute of General Medical Sciences (R01 GM124038)
- Gary Yellen
National Institute of Neurological Disorders and Stroke (F32 NS116105)
- Dylan J Meyer
National Institute of Neurological Disorders and Stroke (F32 NS100331)
- Carlos Manlio Díaz-García
Harvard Mahoney Neuroscience Institute (Postdoctoral Fellowship)
- Dylan J Meyer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: All experiments were performed in compliance with the NIH Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act. The Harvard Medical Area Standing Committee on Animals approved all procedures involving animals. (Animal Welfare Assurance Number A3431-01, Protocol IS00001113-3).
Copyright
© 2022, Meyer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The Na+/K+ pump dominates control of glycolysis in hippocampal dentate granule cells
eLife 11:e81645.
https://doi.org/10.7554/eLife.81645
