PKA and PKC partially rescue long QT type 1 phenotype by restoring channel-PIP2 interactions

Channels
Alessandra MatavelCoeli M Lopes

Abstract

Long-QT syndrome causes torsade de pointes arrhythmia, ventricular fibrillation, and sudden death. The most commonly inherited form of long-QT syndrome, LQT1, is due to mutations on the potassium channel gene KCNQ1, which forms one of the main repolarizing cardiac K(+) channels, IKs. IKs has been shown to be regulated by both beta-adrenergic receptors, via protein kinase A (PKA), and by Gq protein coupled receptors (GqPCR), via protein kinase C (PKC) and phosphatidylinositol 4,5-bisphosphate (PIP(2)). These regulatory pathways were shown to crosstalk, with PKA phosphorylation increasing the apparent affinity of IKs to PIP(2). Here we study the effects of LQT1 mutations in putative PIP(2)-KCNQ1 interaction sites on regulation of IKs by PKA and GqPCR. The effect of the LQT1 mutations on IKs regulation was tested for mutations in conserved, positively charged amino acids, located in four distinct cytoplamic domains of the KCNQ1 subunit: R174C (S2-S3), R243C (S4-S5), R366Q (proximal c-terminus) and R555C (distal c-terminus). Mutations in the c-terminus of IKs (both proximal and distal) enhanced channel sensitivity to changes in membrane PIP(2) levels, consistent with a decrease in apparent channel-PIP(2) affinity. These mutant chan...Continue Reading

Citations

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Dec 6, 2014·Journal of Molecular and Cellular Cardiology·Jin O-UchiCoeli M Lopes
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Jul 18, 2020·Communications Biology·Yongfeng LiuJianmin Cui
Dec 14, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Jerri ChenThomas V McDonald
Apr 1, 2011·Science Translational Medicine·Christian JonsCoeli M B Lopes

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