Berberine induces hERG channel deficiency through trafficking inhibition
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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.
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Two mechanisms may reconcile the discrepancy between hERG-block potency and clinical QT signal: trafficking-dependent reduction in hERG surface expression and pharmacokinetic amplification when berberine is combined with inhibitors of its own metabolism or other QT-prolonging agents.
“Two mechanisms may reconcile the discrepancy: trafficking-dependent reduction in hERG surface expression, which develops over prolonged exposure and at far lower concentrations [85], and pharmacokinetic amplification when berberine is combined with inhibitors of its own metabolism or with other QT-prolonging agents.”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [85]
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“…reconcile the discrepancy: trafficking-dependent reduction in hERG surface expression, which develops over prolonged exposure and at far lower concentrations [85], and pharmacokinetic amplification when berberine is combined with inhibitors of its own metabolism or with other QT-prolonging agents.”
- Authors
- Zhang, K., Zhi, D., Huang, T., Gong, Y., Yan, M., Liu, C., Wei, T., Dong, Z., Li, B., & Yang, B.
- Affiliations
- Harbin Medical University (CN)
- ORCID
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2014
- Volume
- 34
- Issue
- 3
- Pages
- 691-702
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2076769226
- Cited by
- 26
- References
- 27
- Citations by year
- 2026: 4 · 2025: 1 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 3
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (31173050, 81121003, 30973530, 81230081)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Keywords
- berberine, hERG, IKr, channel trafficking, endoplasmic reticulum retention, unfolded protein response, HSP90, HSP70, ATF6, calnexin, calreticulin, ubiquitination, protein degradation, action potential repolarization
- MeSH terms
- ERG1 Potassium Channel, Animals, Berberine, Female, Fluorescent Antibody Technique, Guinea Pigs, Humans, Male, Blotting, Western, Protein Transport, Ether-A-Go-Go Potassium Channels, HEK293 Cells
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