Munoz C et al. (2012), Stimulation of HERG channel activity by β-catenin.

XB-ART-45795

PLoS One 2012 Jan 01;78:e43353. doi: 10.1371/journal.pone.0043353.

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Stimulation of HERG channel activity by β-catenin.

Munoz C , Saxena A , Pakladok T , Bogatikov E , Wilmes J , Seebohm G , Föller M , Lang F .

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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.

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Species referenced: Xenopus
Genes referenced: cdh2 ctnnb1 kcnh2

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	Figure 2. The effect of ß-catenin on HERG currents is not modified by actinomycin D.Arithmetic means±SEM (n = 9–13) of the normalized outward tail current following a depolarization to +80 mV recorded in oocytes injected with cRNA encoding HERG (white bars) or with RNA encoding HERG and ß-catenin (black bars), incubated for 24 hours without (left bars) or with (right bars) 10 µM actinomycin D prior to the measurement. *indicates statistical significance (p<0.05) from the absence of ß-catenin cRNA.
	Figure 3. ß-catenin increases the surface abundance of HERG.Arithmetic means±SEM (n = 19–56) of the normalized HA-dependent surface chemiluminescence of oocytes injected with H20 (1st bar), with cRNA encoding ß-catenin (2nd bar), encoding HERG (3rd bar) or encoding both, HERG and ß-catenin (4th bar). ***indicates statistical significance (p<0.001) from the absence of ß-catenin cRNA.
	Figure 4. The effect of Brefeldin A on ß-catenin-stimulated HERG currents.Arithmetic means±SEM (n = 15–19) of the normalized outward tail current following depolarization to +80 mV recorded in oocytes injected with cRNA encoding HERG (white bars) or with cRNA encoding HERG and ß-catenin (black bars), prior to (0 days) and following incubation for 24 hours (1 day) or 48 hours (2 days) with 5 µM Brefeldin A prior to the measurement. , *indicate statistical significance (p<0.01, p<0.001) from the absence of ß-catenin cRNA.
	Figure 5. HERG currents are insensitive to truncated ß-catenin1–530 and stimulated by N-cadherin.Arithmetic means ± SEM (n = 10–20) of the normalized outward tail current following depolarization to +80 mV and recorded in oocytes injected with water (white bar), or with cRNA encoding HERG (dark grey bar) with ß-catenin (first black bar) or with the truncated mutant ß-catenin1–530 (second black bar), without and with co-expression of N-cadherin (dotted dark grey bars). , **indicate statistical significance (p<0.05, p<0.001) from the absence of HERG cRNA, # (p<0.05) indicates statistical significance from the absence of N-cadherin.
	Figure 1. ß-catenin increases HERG current. A. Original tracings recorded in oocytes injected with H20 (1), with cRNA encoding HERG (2) or HERG coexpressing ß-catenin (3). The oocytes were depolarized from −80 mV holding potential to different voltages followed by a 500 ms pulse to −60 mV evoking outward tail currents. The small insert displays the applied voltage protocol. B. Arithmetic means±SEM (n = 8–11) of the normalized outward tail current following a depolarization to +80 mV recorded in oocytes injected with H20 (left bar), with cRNA encoding HERG (middle bar) or with RNA encoding HERG and ß-catenin (right bar). * indicates statistical significance (p<0.05) from the absence of ß-catenin cRNA. C. IV curves of outward tail currents illustrated in B (upper panel) and IV curves of outward tail currents following normalization to the maximal tail current of the respective group (lower panel).

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