BACKGROUND: The human ether-à-go-go-related gene (hERG 1a) potassium channel is 
critical for cardiac repolarization. hERG 1b, another variant subunit, 
co-assembles with hERG 1a, modulates channel biophysical properties and plays an 
important role in repolarization. Mutations of hERG 1a lead to type 2 long QT 
syndrome (LQT2), and increased risk for fatal arrhythmias. The functional 
consequences of these mutations in the presence of hERG 1b are not known.
OBJECTIVE: To investigate whether hERG 1a mutants exert dominant negative gating 
and trafficking defects when co-expressed with hERG 1b.
METHODS: Electrophysiology, co-immunoprecipitation, and fluorescence resonance 
energy transfer (FRET) experiments in HEK293 cells and guinea pig cardiomyocytes 
were used to assess the mutants on gating and trafficking. Mutations of 1a-G965X 
and 1a-R1014X, relevant to gating and trafficking were introduced in the 
C-terminus region.
RESULTS: The hERG 1a mutants when expressed alone did not result in decreased 
current amplitude. Compared to wild-type hERG 1a currents, 1a-G965X currents 
were significantly larger, whereas those produced by the 1a-R1014X mutant were 
similar in magnitude. Only when co-expressed with wild-type hERG 1a and 1b did a 
mutant phenotype emerge, with a marked reduction in surface expression, current 
amplitude, and a corresponding positive shift in the V1/2 of the activation 
curve. Co-immunoprecipitation and FRET assays confirmed association of mutant 
and wild-type subunits.
CONCLUSION: Heterologously expressed hERG 1a C-terminus truncation mutants, 
exert a dominant negative gating and trafficking effect only when co-expressed 
with hERG 1b. These findings may have potentially profound implications for LQT2 
therapy.