PT  - JOURNAL ARTICLE
AU  - Brian P. Delisle
AU  - Jessica K. Slind
AU  - Jennifer A. Kilby
AU  - Corey L. Anderson
AU  - Blake D. Anson
AU  - Ravi C. Balijepalli
AU  - David J. Tester
AU  - Michael J. Ackerman
AU  - Timothy J. Kamp
AU  - Craig T. January
TI  - Intragenic Suppression of Trafficking-Defective KCNH2 Channels Associated with Long QT Syndrome
AID  - 10.1124/mol.105.012914
DP  - 2005 Jul 01
TA  - Molecular Pharmacology
PG  - 233--240
VI  - 68
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/68/1/233.short
4100  - http://molpharm.aspetjournals.org/content/68/1/233.full
SO  - Mol Pharmacol2005 Jul 01; 68
AB  - 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 IKCNH2 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.