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Aims: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. Methods and Results: hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes. Conclusion: Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.

It has been reported that earthquake b‐values decrease linearly with the differential stresses in the continental crust and subduction zones. Here we report a regression‐derived relation between earthquake b‐values and crustal stresses using the Anderson fault parameter (Aϕ) in a young orogenic belt of Taiwan. This regression relation is well established by using a large and complete earthquake catalog for Taiwan. The data set consists of b‐values and Aϕ values derived from relocated earthquakes and focal mechanisms, respectively. Our results show that b‐values decrease linearly with the Aϕ values at crustal depths with a high correlation coefficient of −0.9. Thus, b‐values could be used as stress indicators for orogenic belts. However, the state of stress is relatively well correlated with the surface geological setting with respect to earthquake b‐values in Taiwan. Temporal variations in the b‐value could constitute one of the main reasons for the spatial heterogeneity of b‐values. We therefore suggest that b‐values could be highly sensitive to temporal stress variations.