Protein Kinase A-Dependent Biophysical Phenotype for V227F-KCNJ2 Mutation in Catecholaminergic Polymorphic Ventricular Tachycardia
Key result
The V227F KCNJ2 mutation exhibited a latent loss of function phenotype, causing marked reduction of outward I(K1) upon PKA-dependent phosphorylation compared with wild-type channels.
Population
Cos-1 cells expressing Kir2.1-wild-type (WT) and V227F channels
Comparison
Protein kinase A-stimulating cocktail composed… vs Kir2.1-WT channels and basal conditions
Design
Preclinical
Authors
Discussion
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Implication
May explain adrenergic arrhythmia triggers in CPVT; hypothesis-generating and leaves open human relevance.
Structured PICO
P
Population
Cos-1 cells expressing Kir2.1-wild-type (WT) and V227F channels
E
Exposure
Protein kinase A (PKA)-stimulating cocktail composed of forskolin and 3-isobutyl-1-methylxanthine
C
Comparator
Kir2.1-WT channels and basal conditions
O
Outcome
I(K1) current measured by voltage clampsurrogate
The KCNJ2 V227F mutation exhibits a latent loss of function dependent on PKA phosphorylation, providing a mechanism for I(K1) dysfunction during adrenergic stress in catecholaminergic polymorphic ventricular tachycardia.
Cite This Study
Vega et al. (2009) studied Catecholaminergic polymorphic ventricular tachycardia. V227F KCNJ2 mutation and PKA stimulation vs. Kir2.1-wild-type (WT) channels was evaluated on I(K1) current reduction. The V227F KCNJ2 mutation exhibited a latent loss of function phenotype, causing marked reduction of outward I(K1) upon PKA-dependent phosphorylation compared with wild-type channels.