Molecular correlates of cardiac potassium currents
To fully understand the repolarizing currents that end each heart-beat in a timely fashion, essential for rhythmic pumping of the heart, one must understand the molecular composition of the potassium channels that generate these currents. A main focus of my laboratory is to determine the cardiac role of a family of five, single transmembrane domain potassium channel ancillary subunits called the MinK-related peptides (MiRPs, encoded by KCNE genes). MiRPs form complexes with the pore-forming alpha subunits of potassium channels, modifying many aspects of their function and cell biology. Because the cardiac physiology of humans is in many ways very different to that of genetically-tractable model organisms such as mice, we use a two-pronged approach to investigating the cardiac roles of MiRPs. On the one hand, we collaborate with human geneticists to identify KCNE gene mutations linked to cardiac arrhythmias, then study the mutant gene products using heterologous systems. On the other hand, we develop mouse models with KCNE genes deleted, and study them using electrophysiological, biochemical, and molecular biological techniques. Relevant articles McCrossan ZA, Roepke TK, Lewis A, Panaghie G, Abbott GW. (2009) Regulation of the Kv2.1 potassium channel by MinK and MiRP1. J. Membr Biol. (2009) 228(1):1-14. PMID: 19219384
Xu X, Kanda VA, Choi E, Panaghie G, Roepke TK, Gaeta SA, Christini DJ, Lerner DJ, Abbott GW. (2009) MinK-dependent internalization of the IKs potassium channel. Cardiovascular Research 82(3):430-8
Roepke TK, Kontogeorgis A, Ovanez C, Xu X, Young JB, Purtell K, Goldstein PA, Christini DJ, Peters NS, Akar FG, Gutstein DE, Lerner DJ, Abbott GW. (2008) Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f. FASEB J. 22(10):3648-60 PMID: 18603586
Gordon E, Panaghie G, Deng L, Bee KJ, Roepke TK, Krogh-Madsen T, Christini DJ, Ostrer H, Basson CT, Chung W, Abbott GW. A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance. Cardiovasc Res. 2008 Jan;77(1):98-106. Epub 2007 Oct 4. PMID: 18006462
Abbott GW, Xu X, Roepke TK. Impact of ancillary subunits on ventricular repolarization. J Electrocardiol. 2007 Nov-Dec;40(6 Suppl):S42-6. PMID: 17993327
Abbott G.W. & Roepke, T.K. Pharmacogenetics of drug-induced arrhythmias. Expert Review of Clinical Pharmacology (in press), 2007
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 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 McCrossan ZA & Abbott G.W. The MinK-Related Peptides Neuropharmacology 47 (6) 787-821, 2004 Anantharam A, Markowitz SM, Abbott G.W. Pharmacogenetic considerations in diseases of cardiac ion channels. J Pharmacol Exp Ther. 307(3):831-8, 2003. Abbott G.W., Goldstein SA. Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. FASEB J. 2002 Mar;16(3):390-400, 2002. Abbott G.W. & Goldstein, S.A.N. The KCNE superfamily of potassium channel subunits: physiology and pathophysiology of the MinK-related peptides (MiRPs). Molecular Interventions 1:95-107, 2001. Abbott G.W., Goldstein, S.A.N., & Sesti, F. Do all voltage-gated potassium channels employ MiRPs? Circulation Research 88:981-983, 2001. 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. Abbott G.W. and Goldstein, S.A.N. A superfamily of small potassium channel subunits: form and function of the MinK-related peptides (MiRPs). Q. Revs. Biophys. 31, 357-398, 1998
