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Cardiac potassium inward rectifier Kir2: Review of structure, regulation, pharmacology, and arrhythmogenesis

Journal

HEART RHYTHM
Volume 18, Issue 8, Pages 1423-1434

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2021.04.008

Keywords

KCNJ2; KCNJ2 mutation; Kir2; Macromolecular complex; Pharmacology; Potassium inward rectifier

Funding

  1. National Institutes of Health (NIH) [R01 HL128598, R01 HL139738-01]

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The potassium inward rectifier channel Kir2 is crucial for cardiac repolarization and membrane stability. Mutations in related genes can lead to sudden cardiac death syndromes. Research focuses on the structure, physiology, and pharmacology of Kir2 channels, as well as their implications for atrial fibrillation treatment and drug safety testing.
Potassium inward rectifier channel Kir2 is an important component of terminal cardiac repolarization and resting membrane stability. This functionality is part of balanced cardiac excitability and is a defining feature of excitable cardiac membranes. Gain-of-function or loss-of-function mutations in KCNJ2, the gene encoding Kir2.1, cause genetic sudden cardiac death syndromes, and loss of the Kir2 current I-K1 is a major contributing factor to arrhythmogenesis in failing human hearts. Here we provide a contemporary review of the functional structure, physiology, and pharmacology of Kir2 channels. Beyond the structure and functional relationships, we will focus on the elements of clinically used drugs that block the channel and the implications for treatment of atrial fibrillation with I-K1 -blocking agents. We will also review the clinical disease entities associated with KCNJ2 mutations and the growing area of research into associated arrhythmia mechanisms. Lastly, the presence of Kir2 channels has become a tipping point for electrical maturity in induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) and highlights the significance of understanding why Kir2 in iPS-CMs is important to consider for Comprehensive In Vitro Proarrhythmia Assay and drug safety testing.

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