The Yellen laboratory studies the molecular physiology of potassium 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. We then express these cloned channels in cell lines and study them using the electrophysiological method of patch recording. The modified channels are probed for changes in their function using channel inhibitors and using chemical modifying agents. One particularly useful strategy is the identification of the Òmoving partsÓ of the channel by introducing cysteine residues at various positions and then monitoring changes in their accessibility to chemical modification during the process of channel gating.
Using these methods, we have identified the pore-forming region of K+ channels and specific sites in this region important for the interaction of inhibitors. We have also studied the mechanisms of inactivation gating, which are important for producing rhythmic electrical activity. For the slow (C-type) inactivation mechanism, we now know details of the conformational change at the level of individual amino acids of the outer mouth of the channel. We have also discovered several new ways in which this inactivation process can be modulated by drugs or by changes in extracellular potassium concentrations (which can occur in seizure states). Recently we discovered that a mechanism similar to C-type inactivation is responsible for the inward-rectification behavior of HERG, a human cardiac K+ channel implicated in an inherited cardiac arrhythmia.
Selected Publications:
Baukrowitz, T., and Yellen, G. (1996). Use-dependent blockers and the exit rate of the last ion from the multi-ion pore of a K+ channel. Science 271:653-656.
Smith, P.L., T. Baukrowitz, and Yellen, G. (1996). The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379:833-836.
Liu, Y., M. E. Jurman, and Yellen, G. (1996). Dynamic rearrangement of the outer mouth of a K+ channel during gating. Neuron (in press).