Long QT2 mutation on the Kv11.1 ion channel inhibits current activity by ablating a protein kinase Calpha consensus site Journal Article


Authors: Donovan, A. J.; Lansu, K.; Williams, J. G.; Denning, M. F.; Gentile, S.
Article Title: Long QT2 mutation on the Kv11.1 ion channel inhibits current activity by ablating a protein kinase Calpha consensus site
Abstract: Mutations that inhibit Kv11.1 ion channel activity contribute to abnormalities of cardiac repolarization that can lead to long QT2 (LQT2) cardiac arrhythmias and sudden death. However, for most of these mutations, nothing is known about the molecular mechanism linking Kv11.1 malfunction to cardiac death. We have previously demonstrated that disease-related mutations that create consensus sites for kinases on ion channels can dramatically change ion channel activity. Here, we show that a LQT2-associated mutation can inhibit Kv11.1 ion channel activity by perturbing a consensus site for the Ser/Thr protein kinase C alpha (PKCalpha). We first reveal by mass spectrometry analysis that Ser890 of the Kv11.1 ion channel is phosphorylated. Then, we demonstrate by a phospho-detection immunoassay combined with genetic manipulation that PKCalpha phosphorylates Ser890. Furthermore, we show that Ser890 phosphorylation is associated with an increase in Kv11.1 membrane density with alteration of recovery from inactivation. In addition, a newly discovered and as yet uncharacterized LQT2-associated nonsynonymous single nucleotide polymorphism 2660 G-->A within the human ether-a-go-go-related gene 1 coding sequence, which replaces arginine 887 with a histidine residue (R887H), strongly inhibits PKCalpha-dependent phosphorylation of residue Ser890 on Kv11.1, and ultimately inhibits surface expression and current density. Taken together, our data provide a functional link between this channel mutation and LQT2.
Keywords: Pathology
Journal Title: Molecular pharmacology
Volume: 82
Issue: 3
ISSN: 1521-0111; 0026-895X
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 428
End Page: 437
Language: eng
DOI/URL:
Notes: ID: 12560; JID: 0035623; 2012/05/31 [aheadofprint]; ppublish