Elsevier

Heart Rhythm

Volume 18, Issue 8, August 2021, Pages 1423-1434
Heart Rhythm

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

https://doi.org/10.1016/j.hrthm.2021.04.008Get rights and content
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open access

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 IK1 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 IK1-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.

Keywords

KCNJ2
KCNJ2 mutation
Kir2
Macromolecular complex
Pharmacology
Potassium inward rectifier

Cited by (0)

Funding sources: This work was funded in part by National Institutes of Health (NIH) Grants R01 HL128598 and R01 HL139738-01 to Dr Eckhardt; Dr Eckardt is funded in part by the Gary and Marie Weiner Professor in Cardiovascular Medicine Research. Disclosures: The authors have no conflicts of interest to disclose.