The transient outward current I to is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary β subunit KCNE2 recently was shown to modulate I to .The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to I to .The functional interaction between Kv4.3 (α subunit of human I to ) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques.Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac I to . Both M54T and I57T variants significantly increased I to current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation.The study results suggest that KCNE2 plays a critical role in the normal function of the native I to channel complex in human heart and that M54T and I57T variants lead to a gain of function of I to , which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.