Pathways of HERG inactivation

• Published in: American journal of physiology. Heart and circulatory physiology 1999-07, Vol.277 (1), p.H199-H210
• Main Authors: Kiehn, Johann, Lacerda, Antonio E, Brown, Arthur M
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.1999.277.1.h199

Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998 The rapid, repolarizing K + current in cardiomyocytes ( I Kr ) has unique inwardly rectifying properties that contribute importantly to the downstroke of the cardiac action potential. The human ether-à-go-go -related gene ( HERG ) expresses a macroscopic current virtually identical to I Kr , but a description of the single-channel properties that cause rectification is lacking. For this reason we measured single-channel and macropatch currents heterologously expressed by HERG in Xenopus oocytes. Our experiments had two main findings. First, the single-channel current-voltage relation showed inward rectification, and conductance was 9.7 pS at 100 mV and 3.9 pS at 100 mV when measured in symmetrical 100 mM K + solutions. Second, single channels frequently showed no openings during depolarization but nevertheless revealed bursts of openings during repolarization. This type of gating may explain the inward rectification of HERG currents. To test this hypothesis, we used a three-closed state kinetics model and obtained rate constants from fits to macropatch data. Results from the model are consistent with rapid inactivation from closed states as a significant source of HERG rectification. rapid repolarizing cardiac potassium current; kinetics; activation