Intragenic suppression of trafficking-defective KCNH2 channels associated with long QT syndrome

Brian P. Delisle, Jessica K. Slind, Jennifer A. Kilby, Corey L. Anderson, Blake D. Anson, Ravi C. Balijepalli, David J. Tester, Michael J. Ackerman, Timothy J. Kamp, Craig T. January

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Mutations in the KCNH2 or human ether-a-go-go-related gene-encoded K + channel reduce functional KCNH2 current (IKCNH2) to cause long QT syndrome (LQT2) by multiple mechanisms, including defects in intracellular transport (trafficking). Trafficking-deficient, or class 2, LQT2 mutations reduce the Golgi processing and surface membrane expression of KCNH2 channel proteins. Drugs that associate with pore-S6 intracellular drug binding domain of KCNH2 channel proteins to cause high-affinity block of I KCNH2 also can increase the processing of class 2 LQT2 channel proteins through the secretory pathway. We used a strategy of intragenic suppression to test the hypothesis that amino acid substitutions in the putative drug binding domain at residue Y652 could compensate for protein folding abnormalities caused by class 2 LQT2 mutations. We found that the Y652C substitution, and to lesser extent the Y652S substitution, resulted in intragenic suppression of the class 2 LQT2 G601S phenotype; these substitutions increased Golgi processing of G601S channel proteins. The Y652C substitution also caused intragenic suppression of the class 2 LQT2 V612L and F640V phenotypes but not the LQT2 N470D or F805C phenotypes. These are the first findings to demonstrate that a single amino acid substitution in the putative KCNH2 drug binding domain can cause intragenic suppression of several LQT2 mutations.

Original languageEnglish (US)
Pages (from-to)233-240
Number of pages8
JournalMolecular pharmacology
Volume68
Issue number1
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Delisle, B. P., Slind, J. K., Kilby, J. A., Anderson, C. L., Anson, B. D., Balijepalli, R. C., Tester, D. J., Ackerman, M. J., Kamp, T. J., & January, C. T. (2005). Intragenic suppression of trafficking-defective KCNH2 channels associated with long QT syndrome. Molecular pharmacology, 68(1), 233-240. https://doi.org/10.1124/mol.105.012914