Impact of ancillary subunits on ventricular repolarization

Voltage-gated potassium (Kv) channels generate the outward K(+) ion currents that constitute the primary force in ventricular repolarization. Voltage-gated potassium channels comprise tetramers of pore-forming alpha subunits and, in probably most cases in vivo, ancillary or beta subunits that help define the properties of the Kv current generated. Ancillary subunits can be broadly categorized as cytoplasmic or transmembrane and can modify Kv channel trafficking, conductance, gating, ion selectivity, regulation, and pharmacology. Because of their often profound effects on Kv channel function, studies of the molecular correlates of ventricular repolarization must take into account ancillary subunits as well as alpha subunits. Cytoplasmic ancillary subunits include the Kv beta subunits, which regulate a range of Kv channels and may link channel gating to redox potential, and the KChIPs, which appear most often associated with Kv4 subfamily channels that generate the ventricular I(to) current. Transmembrane ancillary subunits include the MinK-related proteins (MiRPs) encoded by KCNE genes, which modulate members of most Kv alpha subunit subfamilies, and the putative 12-transmembrane domain KCR1 protein, which modulates hERG. In some cases, such as the ventricular I(Ks) channel complex, it is well established that the KCNQ1 alpha subunit must coassemble with the MinK (KCNE1) single-transmembrane domain ancillary subunit for recapitulation of the characteristic, unusually slowly-activating I(Ks) current. In other cases, it is not so clear-cut, and in particular, the roles of the other MiRPs (1-4) in regulating cardiac Kv channels such as KCNQ1 and hERG in vivo are under debate. MiRP1 alters hERG function and pharmacology, and inherited MiRP1 mutations are associated with inherited and acquired arrhythmias, but controversy exists over the native role of MiRP1 in regulating hERG (and therefore ventricular I(Kr)) in vivo. Some ancillary subunits may exhibit varied expression to shape spatial Kv current variation, for example, KChIP2 and the epicardial-endocardial I(to) current density gradient. Indeed, it is likely that most native ventricular Kv channels exhibit temporal and spatial heterogeneity of subunit composition, complicating both modeling of their functional impact on the ventricular action potential and design of specific current-targeted compounds. Here, we discuss current thinking and lines of experimentation aimed at resolving the complexities of the Kv channel complexes that repolarize the human ventricular myocardium.