Abstract
The multifunctional protein ß-catenin governs as transcription factor the expression of a wide variety of genes relevant for cell proliferation and cell survival. In addition, ß-catenin is localized at the cell membrane and may influence the function of channels. The present study explored the possibility that ß-catenin participates in the regulation of the HERG K+ channel. To this end, HERG was expressed in Xenopus oocytes with or without ß-catenin and the voltage-gated current determined utilizing the dual electrode voltage clamp. As a result, expression of ß-catenin markedly upregulated HERG channel activity, an effect not sensitive to inhibition of transcription with actinomycin D (10 µM). According to chemiluminescence, ß-catenin may increase HERG channel abundance within the oocyte cell membrane. Following inhibition of channel insertion into the cell membrane by brefeldin A (5 µM) the decay of current was similar in oocytes expressing HERG together with ß-catenin to oocytes expressing HERG alone. The experiments uncover a novel function of APC/ß-catenin, i.e. the regulation of HERG channels.
Highlights
The multifunctional protein ß-catenin is involved in the regulation cell proliferation and tumor growth [1,2]. ß-catenin further participates in the physiology and pathophysiology of cardiac hypertrophy [3,4,5,6]. ß-catenin degradation is initiated following phosphorylation by glycogen synthase kinase 3 beta (GSK3ß) [7,8], a kinase counteracting cardiac hypertrophy [9], inhibiting apoptosis and fibrosis and increasing cardiac contractility [10,11]
SS-catenin may enter the nucleus and stimulate the expression of several genes important for cell proliferation [13,14]. ß-cateninstimulated genes include the serum and glucocorticoid inducible kinase SGK1 [15,16], which is required for cardiac fibrosis following mineralocorticoid excess [17]. ß-catenin may further be localized at intercalated disks [18], bind to cadherin [19] and play a role in the regulation of gap junctions [20]
The tail currents that were normalized to the maximum peak tail current of the respective group to investigate kinetics were not significantly modified by the coexpression of ß-catenin, i.e. the voltage evoking half maximal peak tail currents was similar in HERG expressing oocytes with or without additional expression of ß-catenin
Summary
The multifunctional protein ß-catenin is involved in the regulation cell proliferation and tumor growth [1,2]. ß-catenin further participates in the physiology and pathophysiology of cardiac hypertrophy [3,4,5,6]. ß-catenin degradation is initiated following phosphorylation by glycogen synthase kinase 3 beta (GSK3ß) [7,8], a kinase counteracting cardiac hypertrophy [9], inhibiting apoptosis and fibrosis and increasing cardiac contractility [10,11]. The multifunctional protein ß-catenin is involved in the regulation cell proliferation and tumor growth [1,2]. SS-catenin further participates in the physiology and pathophysiology of cardiac hypertrophy [3,4,5,6]. SS-catenin may enter the nucleus and stimulate the expression of several genes important for cell proliferation [13,14]. The present study explored the possibility that ß-catenin participates in the regulation of the human ether-a-go-go (HERG, Kv11.1) channel, which is critically important for the shaping of the cardiac action potential [26,27] and by the same token is essential for the proliferation of some tumor cells [28,29]. The results reveal that the coexpression of ß-catenin leads to marked upregulation of HERG activity by enhancing the plasma membrane abundance of the channel protein
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