Gary Yellen, Ph.D.
Professor of Neurobiology
A major research focus of our lab was inspired by a remarkably effective but poorly understood therapy for epilepsy: the ketogenic diet. Used mainly for the many patients with drug-resistant epilepsy, this high fat, very low carbohydrate diet produces a dramatic reduction or elimination in seizures for most patients. We are investigating the possible role of metabolically-sensitive K+ channels (KATP channels) in the mechanism of the diet, and learning about their basic role in neuronal firing. We have discovered that certain fuel molecules that appear in the blood of people on the ketogenic diet – ketone bodies – can produce opening of KATP channels in various central neurons, which slows action potential firing and may contribute to the anticonvulsant mechanism.
How does ketone body metabolism lead to KATP channel opening? 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 glycolytic ATP production is particularly effective in preventing KATP channels from opening. To investigate this hypothesis and other questions in cellular metabolism, we are developing a series of fluorescent biosensors. Our first such sensor lets us visualize the local ratio of ATP:ADP in living cells. We are targeting this sensor to different cellular locations (plasma membrane, cytoplasm, mitochondria) to learn how energy production and consumption varies locally within neurons and other cells. We are also working on sensors for the basic metabolites NADH and NADPH, to get a more complete picture of metabolic regulation.
This research involves electrophysiology and imaging of cultured neurons and brain slices. We also use knockout mice to investigate specific hypotheses about the connection between neuronal metabolism, excitability, and seizures.
We also study the “moving parts” of functional ion channel proteins using single channel biophysics and directed mutagenesis. One strategy we use is to introduce individual cysteine residues into the channel protein; these cysteines serve as targets for chemical modification and for metal binding. Our ability to modify the introduced cysteines in different conformational states gives specific information about the functional motions of the protein. These methods are now being applied to elucidate the unusual gating of pacemaker channels, which are important generators of rhythmic electrical behavior in the heart and brain.
For a complete listing of Gary Yellen's publications on PubMed, click here.