Research Interests:

The Yellen laboratory studies the molecular physiology of voltage-gated channels and the molecular basis of drug interactions with these channels. Voltage-activated potassium channels are important in the nerve action potential and in regulating rhythmic electrical activity in the nervous system. Inherited defects in K+ channels have been shown to result in seizure disorders or in cardiac arrhythmias.

Our work is directed at understanding the basic molecular function of these channels and the ways in which inhibitors or modulators interact with these functions. We use site-directed mutagenesis to produce channels with designed alterations in their structure. By systematic mutagenesis, we identified the region of the potassium channel protein that lines the pore through which ions cross the membrane, and the parts of the pore that change during opening and closing. In conjunction with our biophysical studies on the mechanisms of K+ channel inactivation and blockade, these discoveries put us in a position to learn about (and manipulate) the basic mechanism of channel gating at the level of individual amino acids. Another 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 also being applied to elucidate the unusual gating of pacemaker channels, which are important generators of rhythmic electrical behavior in the heart and brain.

A new direction in the lab is work on 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 carb 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. A subproject is the development of new tools for optical monitoring of metabolism. We recently used protein engineering to create a genetically-encoded fluorescent sensor of the ATP/ADP ratio in live cells, and we are working on other monitors of metabolism.

Selected Publications:

Webster, S.M., D. del Camino, J.P. Dekker, and G. Yellen (2004). Intracellular gate opening in Shaker K+ channels defined by high affinity metal bridges. Nature 428: 864-868.

Shin, K.S., C. Maertens, C. Proenza, B.S. Rothberg, and G. Yellen (2004). Inactivation in HCN channels results from reclosure of the activation gate: Desensitization to voltage. Neuron 31: 737-744.

Prole, D.L., and G. Yellen (2006). Reversal of HCN channel voltage dependence via bridging of the S4-S5 linker and post-S6. Journal of General Physiology 128: 273-282.

Ma, W., J. Berg, and G. Yellen. (2007). Ketogenic diet metabolites reduce firing in central neurons by opening KATP channels. Journal of Neuroscience 27: 3618-3625.