Gating and assembly of heteromeric hERG1a/1b channels underlying I_(Kr) in the heart

摘要

Until recently, ion channels generating cardiac I_(Kr) were thought to comprise four identical alpha subunits encoded by the ERG1a transcript. Despite studies identifying another transcript, ERG1b, failure to identify the corresponding protein in native tissue led to the conclusion that the ERGlb subunit is not a constituent of cardiac I_(Kr) channels. Interestingly, hERG1b subunits coexpressed in heterologous systems preferentially form heteromultimers with hERG1a and modify the deactivation gating properties previously attributed to the hERG1a N-terminus. The two subunits are identical except for their divergent N-termini. Moreover, I_(Kr) kinetic properties are more closely mimicked by currents from heteromeric, compared to homomeric, channels. Studies with a new generation of antibodies now show that ERG1b subunits also contribute to I_(Kr) channels in vivo, likely in heteromeric assemblies with ERG1a. Bidirectional co-immunoprecipitation of ERG1a and 1b subunits from canine and human ventricle indicates that the subunits associate in native tissue, where they are also found by immunocytochemistry to localize to the same subcellular compartment. These new findings raise questions as to the role of the respective N-termini in deactivation gating and assembly invivo, as well as the disease mechanisms of mutations causing hERG-linked long QT syndrome, approximately 20% of which reside in the hERG1a N-terminus and have previously been evaluated only in the context of the hERG1a homomers.