Mutant MiRP1 subunits modulate HERG K+ channel gating: a mechanism for pro-arrhythmia in long QT syndrome type 6.
Mutations in KCNE2, which encodes the minK-related protein 1 (MiRP1), are associated with an increased risk of arrhythmias; however, the underlying mechanisms are unknown. MiRP1 is thought to associate with many K+ channel alpha-subunits, including HERG K+ channels, which have a major role in suppressing arrhythmias initiated by premature beats. In this study we have investigated in Chinese hamster ovary (CHO) cells at 37 degrees C the effects of co-expressing HERG K+ channels with either wild-type (WT) MiRP1 or one of three mutant MiRP1 subunits, T8A, Q9E and M54T. The most significant effects of MiRP1 subunits on HERG channels were a more negative steady-state activation for HERG + T8A MiRP1 and a more positive steady-state activation for HERG + M54T MiRP1 compared to either HERG + WT MiRP1 or HERG alone. All three mutants caused a significant slowing of deactivation at depolarised potentials. T8A MiRP1 also caused an acceleration of inactivation and recovery from inactivation compared to HERG + WT MiRP1. During ventricular action potential clamp experiments there was a significant decrease in current in the early phases of the action potential for HERG + WT MiRP1 channels compared to HERG alone. This effect was not as prominent for the mutant MiRP1 subunits. During premature action potential clamp protocols, the T8A and Q9E mutants, but not the M54T mutant, resulted in significantly larger current spikes during closely coupled premature beats, compared to HERG + WT MiRP1. At longer coupling intervals, all three mutants resulted in larger current spikes than HERG alone or HERG + WT MiRP1 channels. It is therefore possible that augmentation of HERG currents in the early diastolic period may be pro-arrhythmic.
Lu
Yu
Y
Physiological Laboratory, University of Cambridge, Cambridge CB2 3EG, UK.
Mahaut-Smith
Martyn P
MP
Huang
Christopher L-H
CL
Vandenberg
Jamie I
JI
D000200:Action Potentials; D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels; D006706:Homeostasis; D015640:Ion Channel Gating; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; C059983:potassium channel protein I(sk)