Small-molecule modulation of potassium channels
Ion channels are an important target both for therapeutic modulation by drugs, and for harmful interactions with drugs and other small molecules. One example of the former is retigabine, an anti-epileptic drug that binds to neuronal KCNQ2-KCNQ3 channels to increase their ability to pass currents particularly at negative potentials, therefore reducing neuronal excitability. An example of the latter is the hERG potassium channel: essential for human ventricular repolarization, but blighted by a unique structure that favors unwanted interaction with, and thus inhibition by, a diverse range of small molecules. Many of these small molecules were used as medications until they were found to cause cardiac arrhythmia due to hERG blockade.
We are studying both aspects of small-molecule interaction with potassium channels. We are examining the effects of MiRP ancillary subunits on potassium channel pharmacology, an important consideration in therapeutic development and avoidance of side-effects, given that many native Kv channels incorporate MiRPs. We are also collaborating with chemists to develop small molecules that interact with potassium channels, both for research purposes, and ultimately to examine therapeutic possibilities.
Relevant articles
Abbott G.W. & Roepke, T.K. Pharmacogenetics of drug-induced arrhythmias. Expert Review of Clinical Pharmacology (in press), 2007
Gordon, E., Cohen, J.L., Engel, R, & Abbott G.W. 1,4-diazabicyclo[2.2.2]octane derivatives: a novel class of voltage-gated potassium channel blockers. Molecular Pharmacology 69(3):718-726, 2006
Panaghie, G., & Abbott G.W. The impact of ancillary subunits on small-molecule interactions with voltage-gated potassium channels. Current Pharmaceutical Design 12(18): 2285-2302, 2006
Abbott G.W. Molecular mechanisms of cardiac potassium channelopathies. Current Pharmaceutical Design 12(28): 3631-3644, 2006
Roepke, T.K, & Abbott G.W. Pharmacogenetics and cardiac ion channels. Vascular Pharmacology 44(2):90-106, 2006
Cacheaux, L.P., Topf, N., Tibbs, G.R., Schaefer, U.R., Levi, R., Harrison, N.L., Abbott G.W. & Goldstein, P. Impairment of HCN channel function by the intravenous general anesthetic propofol. J. Pharm Exp. Ther. 315(2):517-25, 2005
Anantharam A & Abbott G.W. Does hERG coassemble with a beta subunit? Evidence for roles of MinK and MiRP1 in The hERG Cardiac Potassium Channel: structure, function and drug-induced long QT syndrome. Novartis Foundation, London, U.K., 2005
Anantharam A, Markowitz SM, Abbott G.W. Pharmacogenetic considerations in diseases of cardiac ion channels. J Pharmacol Exp Ther. 307(3):831-8, 2003.
Sesti, F., Abbott G.W., Wei, J., Murray, K.T., Saksena, S., Schwartz, P.J., Priori, S.G., Roden, D.M., George, Jr., A.L., & Goldstein, S.A.N. A polymorphism associated with cardiac arrhythmia increases sensitivity to a common antibiotic. Proc. Nat. Acad. Sci. 97:10613-10618, 2000.
Abbott G.W., Sesti, F., Splawski, I., Buck, M.E., Lehmann, M.H., Timothy, K.W., Keating, M.T. & Goldstein, S.A.N. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175-187, 1999.
