Protein kinase a-Dependent biophysical phenotype for V227F-KCNJ2 mutation in catecholaminergic polymorphic ventricular tachycardia

Jonathan C. Makielski, Amanda L. Vega, David J. Tester, Michael J. Ackerman

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Background-KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I K1. KCNJ2 mutations are associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNJ2 missense mutation, V227F, found in a patient with catecholaminergic polymorphic ventricular tachycardia. Methods and Results-Kir2.1-wild-type (WT) and V227F channels were expressed individually and together in Cos-1 cells to measure I K1 by voltage clamp. Unlike typical Andersen-Tawil syndrome-associated KCNJ2 mutations, which show dominant negative loss of function, Kir2.1WT+V227F coexpression yielded I K1 indistinguishable from Kir2.1-WT under basal conditions. To simulate catecholamine activity, a protein kinase A (PKA)-stimulating cocktail composed of forskolin and 3-isobutyl-1-methylxanthine was used to increase PKA activity. This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I K1 compared with Kir2.1-WT. PKA-induced reduction in I K1 was eliminated by mutating the phosphorylation site at serine 425 (S425N). Conclusions-Heteromeric Kir2.1-V227F and WT channels showed an unusual latent loss of function biophysical phenotype that depended on PKA-dependent Kir2.1 phosphorylation. This biophysical phenotype, distinct from typical Andersen-Tawil syndrome mutations, suggests a specific mechanism for PKA-dependent I K1 dysfunction for this KCNJ2 mutation, which correlates with adrenergic conditions underlying the clinical arrhythmia. (Circ Arrhythmia Electrophysiol. 2009;2:540-547.)

Original languageEnglish (US)
Pages (from-to)540-547
Number of pages8
JournalCirculation: Arrhythmia and Electrophysiology
Volume2
Issue number5
DOIs
StatePublished - Oct 2009

Keywords

  • Andersen-Tawil syndrome
  • Arrhythmia (mechanisms)
  • K-channel
  • Long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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