Gary Yellen, Ph.D.

Professor of Neurobiology

Harvard Medical School
Neurobiology, W.A.B. 328
200 Longwood Ave
Boston, MA 02115
Telephone: 617-432-0137
Fax: 617-432-0121 
E-mail: Gary_Yellen@hms.harvard.edu
Predocs: 2 Postdocs: 4 Completed PhD's: 5

All electrical signaling in the nervous system is controlled by ion channels, a class of membrane proteins that form pores through the membrane. Charged ions such as sodium, potassium and calcium pass through ion channels and carry an electrical current. The channels themselves are regulated, so that the pores are only open when the proper chemical or electrical signal is present, and only certain ions can pass through a particular kind of channel. By understanding how channels open and close and how they are regulated, we define the repertoire of molecular changes used by neurons when they signal, sense, and learn.

My laboratory uses single channel biophysics and directed mutagenesis to relate ion channel function to structure. Our studies are focused primarily on voltage-activated potassium channels. 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.

Understanding the functional motions of channel proteins is also giving us insight into the actions of therapeutic drugs that are targeted to ion channels. Many drugs bind with higher affinity to one of the functional states of the channel proteins; this allows the drugs to inhibit channels preferentially when they are in a high activity state. Such "use-dependence" is an important feature of therapeutically useful drugs, and our work is giving new insights into how use-dependence occurs and how it can be altered and improved.

Finally, a new direction in the lab is 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.

References:

• Liu Y, Holmgren M, Jurman ME, Yellen G (1997) Gated access to the pore of a voltage-dependent K+ channel. Neuron 19:175-184.
• Yellen, G. (1998) The moving parts of voltage-gated ion channels. Quarterly Reviews of Biophysics 31:239-296.
• Holmgren, M., Shin KS, Yellen G (1998) The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge. Neuron 21:617-621.
• del Camino, D., Holmgren M, Liu Y, Yellen G. (2000) Blocker protection in the pore of a voltage-gated K+ channel and its structural implications. Nature 403:321-325.
• Yellen G. (2002) The voltage-gated potassium channels and their relatives. Nature 419:35-42.
• Shin KS, Maertens C, Proenza C, Rothberg BS, Yellen G. (2004) Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage. Neuron 41:737-44.
• Webster SM, Del Camino D, Dekker JP, Yellen G. (2004) Intracellular gate opening in Shaker K+ channels defined by high-affinity metal bridges. Nature 428:864-8.