PT  - JOURNAL ARTICLE
AU  - Jun Guo
AU  - Hamid Massaeli
AU  - Wentao Li
AU  - Jianmin Xu
AU  - Tao Luo
AU  - James Shaw
AU  - Lorrie A. Kirshenbaum
AU  - Shetuan Zhang
TI  - Identification of I<sub>Kr</sub> and Its Trafficking Disruption Induced by Probucol in Cultured Neonatal Rat Cardiomyocytes
AID  - 10.1124/jpet.107.120931
DP  - 2007 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 911--920
VI  - 321
IP  - 3
4099  - http://jpet.aspetjournals.org/content/321/3/911.short
4100  - http://jpet.aspetjournals.org/content/321/3/911.full
SO  - J Pharmacol Exp Ther2007 Jun 01; 321
AB  - The human ether-a-go-go-related gene (hERG) encodes a channel that conducts the rapidly activating delayed rectifier K+ current (IKr), which is important for cardiac repolarization. Mutations in hERG reduce IKr and cause congenital long QT syndrome (LQTS). More frequently, common medications can reduce IKr 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 IKr trafficking at the protein level. In the present study, we identified that IKr 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 IKr trafficking and prolonged the cardiac action potential duration. Probucol did not directly block IKr. 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 IKr trafficking. The American Society for Pharmacology and Experimental Therapeutics