Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes

Jun Guo, Hamid Massaeli, Wentao Li, Jianmin Xu, Tao Luo, James Shaw, Lorrie A. Kirshenbaum, Shetuan Zhang

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

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 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 druginduced 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.

Original languageEnglish
Pages (from-to)911-920
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume321
Issue number3
DOIs
Publication statusPublished - 1 Jun 2007
Externally publishedYes

Fingerprint

Probucol
Long QT Syndrome
Cardiac Myocytes
Ether
Genes
Protein Transport
Mutation
Muscle Cells
Action Potentials
Cholesterol
Kidney

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. / Guo, Jun; Massaeli, Hamid; Li, Wentao; Xu, Jianmin; Luo, Tao; Shaw, James; Kirshenbaum, Lorrie A.; Zhang, Shetuan.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 321, No. 3, 01.06.2007, p. 911-920.

Research output: Contribution to journalArticle

Guo, Jun ; Massaeli, Hamid ; Li, Wentao ; Xu, Jianmin ; Luo, Tao ; Shaw, James ; Kirshenbaum, Lorrie A. ; Zhang, Shetuan. / Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 321, No. 3. pp. 911-920.
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