Abstract: AIM:To study the influence of KCNE4 on potassium ion channel KCNQ1 and HERG. METHOD: We constructed KCNE4 expression plasmids and performed whole-cell patch-clamp recording on cells cotransfected with KCNQ1 or HERG to identify potential functional consequences. Immunocytochemistry was used to study protein colocalization. RESULTS: The presence of KCNE4 resulted in a dramatic decrease of the KCNQ1 current and produced almost undetectable currents between -80 mV and +60 mV. KCNQ1-expressing cells showed a slowly activating, noninactivating voltage-dependent current ［current density (24±2.9) pA/pF recorded at +60 mV］. In KCNQ1+KCNE4 co-expressing cells, the current density decreased to (7.3±1.1) pA/pF at +60 mV. Expression of KCNE4 alone did not yield any current. Furthermore, the differences between KCNQ1 and KCNQ1/KCNE4 currents were also found in the time course of activation and deactivation, suggesting that KCNE4 can participate in kinetic control of KCNQ1 channel. Subcellular localization study showed the same plasma membrane fluorescence pattern of KCNQ1 when co-expressed with KCNE4, implying that KCNE4 had no effect on the protein trafficking and localization of KCNQ1. There were no differences between HERG and HERG/KCNE4 in the current density and the kinetics control of HERG channel. CONCLUSION: Our data suggest that KCNE4 dramatically decreases KCNQ1 current density at physiologically relevant potentials and exerts an inhibitory effect on KCNQ1 channel. KCNE4 has no effect on HERG channel.