Article ; Online: Role of the activation gate in determining the extracellular potassium dependency of block of HERG by trapped drugs.
2012 Volume 7, Issue 1, Page(s) 23–33
Abstract: ... Extracellular potassium influences HERG channel inactivation and can alter block of HERG by some drugs ... However, block of HERG by a number of drugs is not sensitive to extracellular potassium. In this study, we show ... that block of WT HERG by bepridil and terfenadine, two drugs previously shown to be trapped inside the HERG ...
| Abstract | Drug induced long QT syndrome (diLQTS) results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases long QT syndrome can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with serum potassium abnormalities due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, and aging. Extracellular potassium influences HERG channel inactivation and can alter block of HERG by some drugs. However, block of HERG by a number of drugs is not sensitive to extracellular potassium. In this study, we show that block of WT HERG by bepridil and terfenadine, two drugs previously shown to be trapped inside the HERG channel after the channel closes, is insensitive to extracellular potassium over the range of 0 mM to 20 mM. We also show that bepridil block of the HERG mutant D540K, a mutant channel that is unable to trap drugs, is dependent on extracellular potassium, correlates with the permeant ion, and is independent of HERG inactivation. These results suggest that the lack of extracellular potassium dependency of block of HERG by some drugs may in part be related to the ability of these drugs to be trapped inside the channel after the channel closes. |
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| MeSH term(s) | Bepridil/metabolism ; Bepridil/pharmacokinetics ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/genetics ; Ether-A-Go-Go Potassium Channels/metabolism ; Humans ; Long QT Syndrome/genetics ; Long QT Syndrome/metabolism ; Potassium/metabolism ; Potassium Channel Blockers/metabolism ; Potassium Channel Blockers/pharmacokinetics ; Terfenadine/metabolism ; Terfenadine/pharmacokinetics |
| Chemical Substances | ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; KCNH2 protein, human ; Potassium Channel Blockers ; Bepridil (755BO701MA) ; Terfenadine (7BA5G9Y06Q) ; Potassium (RWP5GA015D) |
| Language | English |
| Publishing date | 2012-12-06 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2262854-X |
| ISSN | 1933-6969 ; 1933-6969 |
| ISSN (online) | 1933-6969 |
| ISSN | 1933-6969 |
| DOI | 10.4161/chan.22669 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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