Gary Yellen
Gary Yellen, PhD
Professor of Neurobiology

Neuronal Metabolism and Excitability

These projects are inspired by a remarkably effective but poorly understood therapy for epilepsy: the ketogenic diet. We have discovered that certain fuel molecules that appear in the blood of people on the ketogenic diet – ketone bodies – can produce opening of metabolically sensitive KATP channels in various central neurons. Opening of these potassium channels slows action potential firing and may contribute to the anticonvulsant mechanism. Our main hypothesis is that ketone bodies, or other metabolic manipulations, lead to a shift from glycolytic metabolism to other mechanisms of ATP production, and that this shift away from glycolytic ATP production is particularly effective in allowing KATP channels (which are inhibited by ATP) to open.

We aim to learn:

  • When are neuronal KATP channels active, and how do they influence firing and seizures?
  • Is ATP locally compartmented in neurons? In particular, does glycolysis govern ATP:ADP in the submembrane space sensed by KATP channels?
  • How does neuronal metabolism vary with fuel source?
  • What other signals or metabolic changes shift the balance between glycolysis and other metabolic pathways?
  • How does astrocyte metabolism influence neuronal metabolism?

We use electrophysiological and pharmacologic tools, as well as knockout mice. We also are developing a series of new fluorescent biosensors for visualizing metabolite levels in cells -- we already have a sensor for ATP:ADP ratio, and are working on sensors for NADH and NADPH.

In the long run, we would like to understand what it is about the ketogenic diet that prevents epileptic seizures. Because diets (and especially this diet) are notoriously difficult for people to follow, we hope that understanding the physiological basis of such therapy allows us either to fine-tune the dietary manipulation or to find medications that target the same very effective anticonvulsant mechanisms tapped into by the ketogenic diet.

The Moving Parts of Voltage-gated Ion Channels

We use single channel biophysics and directed mutagenesis to relate ion channel function to structure. Often we introduce individual cysteine residues into the channel protein; these cysteines serve as targets for chemical modification and for metal binding. For instance, when introduced at just the right place in the moving parts of the channel protein, a pair of cysteines can be bridged by a metal ion (such as Cd2+). If the metal bridges are compatible with only some of the functional conformations of the channel, they influence gating: for instance, they can lock the channel in an open state or in a closed state.

We have applied this approach, together with looking at the state-dependent rate of chemical modification of cysteines, to learn about the moving parts of both voltage-gated K+ channels and voltage-gated pacemaker (HCN) channels. Our current focus is to learn about coupling between the sensors and gates of these channels: how the nucleotide binding domain and the pore-forming domain interact during gating of HCN channels, and why the HCN channels have a "backward" voltage-dependence.

yellen research"In the long run, we would like to understand what it is about the ketogenic diet that prevents epileptic seizures."

Publications View
Quantitative in vivo imaging of neuronal glucose concentrations with a genetically encoded fluorescence lifetime sensor.
Authors: Authors: Díaz-García CM, Lahmann C, Martínez-François JR, Li B, Koveal D, Nathwani N, Rahman M, Keller JP, Marvin JS, Looger LL, Yellen G.
J Neurosci Res
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Neurons rely on glucose rather than astrocytic lactate during stimulation.
Authors: Authors: Díaz-García CM, Yellen G.
J Neurosci Res
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Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism.
Authors: Authors: Yellen G.
J Cell Biol
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BAD and KATP channels regulate neuron excitability and epileptiform activity.
Authors: Authors: Martínez-François JR, Fernández-Agüera MC, Nathwani N, Lahmann C, Burnham VL, Danial NN, Yellen G.
Elife
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BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy.
Authors: Authors: Foley J, Burnham V, Tedoldi M, Danial NN, Yellen G.
Epilepsia
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Live cell imaging of cytosolic NADH/NAD+ ratio in hepatocytes and liver slices.
Authors: Authors: Masia R, McCarty WJ, Lahmann C, Luther J, Chung RT, Yarmush ML, Yellen G.
Am J Physiol Gastrointest Liver Physiol
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Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells.
Authors: Authors: Hung YP, Teragawa C, Kosaisawe N, Gillies TE, Pargett M, Minguet M, Distor K, Rocha-Gregg BL, Coloff JL, Keibler MA, Stephanopoulos G, Yellen G, Brugge JS, Albeck JG.
Elife
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Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake.
Authors: Authors: Díaz-García CM, Mongeon R, Lahmann C, Koveal D, Zucker H, Yellen G.
Cell Metab
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Cytosolic NADH-NAD(+) Redox Visualized in Brain Slices by Two-Photon Fluorescence Lifetime Biosensor Imaging.
Authors: Authors: Mongeon R, Venkatachalam V, Yellen G.
Antioxid Redox Signal
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The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons.
Authors: Authors: Lutas A, Lahmann C, Soumillon M, Yellen G.
Elife
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