A rich diversity of ion channel genes and families are now known from molecular cloning and genome sequencing efforts. This abundance of ion channel genes poses dual problems: most have unknown functions and few have defined pharmacologies that could be used to dissect their biophysical or physiological mechanisms of action. Indeed, there are entire channel families that are pharmacological orphans. Unraveling the functions of this multitude of ion channels demands the development of new tools for the manipulation of a given ion channel's action in a in a variety of in vivo and in vitro settings.

To accelerate the pace at which ion channel modulators can be discovered and characterized, we are developing approaches for identifying small molecule ion channel blockers as well as a general means to generate high affinity, specific inhibitors and activators of ion channels through the use of molecular evolution and selection methods. Uncovering new modulators would present the necessary tools to unlock a wide range of questions from basic channel biophysics to physiology.

Our lab has recently demonstrated the feasibility of using complementation of a potassium transport deficient strain of yeast as a means to identify ion channel blockers and map their sites of action. Studies of the potassium channel blocker barium, uncovered barium-resistant inward rectifier mutants that challenge current notions about how potassium channels work (Chatelain et al., 2005). These studies also emphasize the utility of using genetic selection approaches for probing ion channel-blocker interactions. Further work in the lab is dedicated to expanding genetic selections to identify a range of small molecule and peptide modifiers of channel activity. Such molecules should provide important tools for research and may help accelerate the development of ion channel-directed drugs.

[1] Structural understanding of ion channel action and regulation
[2] Molecular evolution of ion channel modulators for channels
[3] Structural understanding of membrane proteins that power the cell through their actions in mitochondria