Mouse ERG K(+) Channel Clones Reveal Differences in Protein Trafficking and Function

BACKGROUND: The mouse ether‐a‐go‐go‐related gene 1a (mERG1a, mKCNH2) encodes mERG K(+) channels in mouse cardiomyocytes. The mERG channels and their human analogue, hERG channels, conduct I(Kr). Mutations in hERG channels reduce I(Kr) to cause congenital long‐QT syndrome type 2, mostly by decreasing surface membrane expression of trafficking‐deficient channels. Three cDNA sequences were originally reported for mERG channels that differ by 1 to 4 amino acid residues (mERG‐London, mERG‐Waterston, and mERG‐Nie). We characterized these mERG channels to test the postulation that they would differ in their protein trafficking and biophysical function, based on previous findings in long‐QT syndrome type 2. METHODS AND RESULTS: The 3 mERG and hERG channels were expressed in HEK293 cells and neonatal mouse cardiomyocytes and were studied using Western blot and whole‐cell patch clamp. We then compared our findings with the recent sequencing results in the Welcome Trust Sanger Institute Mouse Genomes Project (WTSIMGP). CONCLUSIONS: First, the mERG‐London channel with amino acid substitutions in regions of highly ordered structure is trafficking deficient and undergoes temperature‐dependent and pharmacological correction of its trafficking deficiency. Second, the voltage dependence of channel gating would be different for the 3 mERG channels. Third, compared with the WTSIMGP data set, the mERG‐Nie clone is likely to represent the wild‐type mouse sequence and physiology. Fourth, the WTSIMGP analysis suggests that substrain‐specific sequence differences in mERG are a common finding in mice. These findings with mERG channels support previous findings with hERG channel structure–function analyses in long‐QT syndrome type 2, in which sequence changes in regions of highly ordered structure are likely to result in abnormal protein trafficking.