ArticleChannels (Austin, Tex.)
Cholesterol regulates HERG K+ channel activation by increasing phospholipase C β1 expression.
Article in Channels (Austin, Tex.). The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- A randomized controlled trial of the short-term effect of rosuvastatin on the corrected QT interval.Scientific reports · 2025Trial
- Effect of the Membrane Environment on Pharmacologic Inhibition of hERG KJACC. Clinical electrophysiology · 2025Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Bacterial toxins and heart function: heat-labileBiophysical reviews · 2023Article
- Long QT: Time to cut cholesterol?International journal of cardiology. Heart & vasculature · 2023Article
- Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B.Advances in experimental medicine and biology · 2023Article
- High-Cholesterol Diet Decreases the Level of Phosphatidylinositol 4,5-Bisphosphate by Enhancing the Expression of Phospholipase C (PLCβ1) in Rat Brain.International journal of molecular sciences · 2020Article
- bSUM: A bead-supported unilamellar membrane system facilitating unidirectional insertion of membrane proteins into giant vesicles.The Journal of general physiology · 2016Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human ether-a-go-go-related gene (HERG) K(+) channel underlies the rapidly activating delayed rectifier K(+) conductance (IKr) during normal cardiac repolarization. Also, it may regulate excitability in many neuronal cells. Recently, we showed that enrichment of cell membrane with cholesterol inhibits HERG channels by reducing the levels of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] due to the activation of phospholipase C (PLC). In this study, we further explored the effect of cholesterol enrichment on HERG channel kinetics. When membrane cholesterol level was mildly increased in human embryonic kidney (HEK) 293 cells expressing HERG channel, the inactivation and deactivation kinetics of HERG current were not affected, but the activation rate was significantly decelerated at all voltages tested. The application of PtdIns(4,5)P2 or inhibitor for PLC prevented the effect of cholesterol enrichment, while the presence of antibody against PtdIns(4,5)P2 in pipette solution mimicked the effect of cholesterol enrichment. These results indicate that the effect of cholesterol enrichment on HERG channel is due to the depletion of PtdIns(4,5)P2. We also found that cholesterol enrichment significantly increases the expression of β1 and β3 isoforms of PLC (PLCβ1, PLCβ3) in the membrane. Since the effects of cholesterol enrichment on HERG channel were prevented by inhibiting transcription or by inhibiting PLCβ1 expression, we conclude that increased PLCβ1 expression leads to the deceleration of HERG channel activation rate via downregulation of PtdIns(4,5)P2. These results confirm a crosstalk between two plasma membrane-enriched lipids, cholesterol and PtdIns(4,5)P2, in the regulation of HERG channels.
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