Journal
CIRCULATION RESEARCH
Volume 89, Issue 1, Pages 33-38Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh1301.093633
Keywords
delayed rectifier potassium channels; Markov chains; action potential; arrhythmia; accessory proteins
Funding
- NHLBI NIH HHS [HLO7227, P50 HL52307, R01 HL60133, R01 HL66381] Funding Source: Medline
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The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the EGG. Mutations in either of the two molecular components of the rapid delayed rectifier (I-K,I-r), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I-K,I-r density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel a subunits.
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