Voltage-gated Kv1.5 channels are expressed in a wide variety of tissues including cardiac myocytes, smooth muscle and tumor cells. Kv1.5 channel activity is modified by N-cadherin, which in turn binds the multifunctional oncogenic protein beta-catenin. The present experiments explored the effect of beta-catenin on Kv1.5 channel activity. To this end, Kv1.5 was expressed in Xenopus oocytes with or without beta-catenin and the voltage-gated Kv current determined by dual electrode voltage clamp. As a result, expression of beta-catenin significantly increased the voltage-gated Kv current at positive potentials. The stimulating effect of beta-catenin on Kv1.5 was not dependent on the stimulation of transcription since it was observed even in the presence of the transcription inhibitor actinomycin D. Specific antibody binding to surface Kv1.5 in Xenopus oocytes revealed that beta-catenin enhances the membrane abundance of Kv1.5. Further experiments with brefeldin A showed that beta-catenin fosters the insertion of Kv1.5 into rather than delaying the retrieval from the plasma membrane. According to electrophysiological recordings with mutant beta-catenin, the effect on Kv1.5 requires the same protein domains that are required for association of beta-catenin with cadherin. The experiments disclose a completely novel function of beta-catenin, i.e. the regulation of Kv1.5 channel activity. (C) 2011 Elsevier Inc. All rights reserved.