Identification of IKr and Its Trafficking Disruption Induced by Probucol in Cultured Neonatal Rat Cardiomyocytes
Autor: | Wentao Li, Jun Guo, Hamid Massaeli, Jianmin Xu, James Shaw, Lorrie A. Kirshenbaum, Shetuan Zhang, Tao Luo |
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Rok vydání: | 2007 |
Předmět: |
Male
ERG1 Potassium Channel congenital hereditary and neonatal diseases and abnormalities Patch-Clamp Techniques Pyridines hERG Probucol Action Potentials Cesium Gene Expression Pharmacology Biology Transfection Cell Line Rats Sprague-Dawley Piperidines medicine Animals Humans Myocyte Myocytes Cardiac cardiovascular diseases Patch clamp RNA Small Interfering Cells Cultured Cell Membrane HEK 293 cells Cardiac action potential Ether-A-Go-Go Potassium Channels Rats Electrophysiology Protein Transport Animals Newborn Cell culture Potassium biology.protein Molecular Medicine Female Anti-Arrhythmia Agents medicine.drug |
Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 321:911-920 |
ISSN: | 1521-0103 0022-3565 |
Popis: | The human ether-a-go-go-related gene (hERG) encodes a channel that conducts the rapidly activating delayed rectifier K(+) current (I(Kr)), which is important for cardiac repolarization. Mutations in hERG reduce I(Kr) and cause congenital long QT syndrome (LQTS). More frequently, common medications can reduce I(Kr) and cause LQTS as a side effect. Protein trafficking abnormalities are responsible for most hERG mutation-related LQTS and are recently recognized as a mechanism for drug-induced LQTS. Whereas hERG trafficking has been studied in recombinant expression systems, there has been no reported study on cardiac I(Kr) trafficking at the protein level. In the present study, we identified that I(Kr) is present in cultured neonatal rat ventricular myocytes and can be robustly recorded using Cs(+) as the charge carrier. We further discovered that 4,4'-(isopropylidenedithio)-bis-(2,6-di-t-butylphenol) (probucol), a cholesterol-lowering drug that induces LQTS, disrupted I(Kr) trafficking and prolonged the cardiac action potential duration. Probucol did not directly block I(Kr). Probucol also disrupted hERG trafficking and did not block hERG channels expressed in human embryonic kidney 293 cells. We conclude that probucol induces LQTS by disrupting ether-a-go-go-related gene trafficking, and that primary culture of neonatal rat cardiomyocytes represents a useful system for studying native I(Kr) trafficking. |
Databáze: | OpenAIRE |
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