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Electrophysiology

Channelosome and intracellular K+ channels in arrhythmia

Nature Cardiovascular Research volume 1, pages 874–875 (2022)Cite this article

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Mutations in Kir2.1 resulting in defects in trafficking to the cardiomyocyte sarcolemma promote arrhythmia in Anderson–Tawil syndrome. Macias and colleagues provide a dual mechanism underlying cardiac arrhythmia that involves chaperoning of voltage-gated Na+ channels and a unique population of intracellular Kir2.1 channels that regulate Ca2+ cycling at the sarcoplasmic reticulum.

K+ inward-rectifying (Kir) channels were first described in 1949 as “anomalously rectified” because they did not behave like ‘proper’ outwardly rectified K+ channels, identified shortly before1. It was later discovered that inward rectification is a result of voltage-dependent blocks that limit the conductance of the channels in the depolarizing range. Kir2 channels, a subfamily of Kir channels, are ubiquitously expressed in mammalian cells, and traditionally, their role has been identified as providing basic maintenance of a stable resting potential of the plasma membrane by keeping K+ close to electrochemical equilibrium. Mutations in Kir2.1 lead to a devastating disease, Andersen–Tawil syndrome (ATS), characterized by cardiac arrhythmias, periodic paralysis and developmental dysmorphisms2,3. An array of Kir2.1 mutations, has been identified in patients with ATS that render the channels non-functional, including mutations in the channel pore; mutations that interfere with Kir2.1 binding to an essential regulator, PIP2; and mutations that prevent proper trafficking of the channels to the plasma membrane3. ATS-related Kir2.1 mutant subunits may retain the ability to co-assemble with the wild-type Kir2.1, thus exerting a dominant-negative effect3. Modeling studies suggested that the loss of Kir2.1 results in the prolongation of the terminal phase of cardiac action–potential repolarization, which was further proposed to underlie the susceptibility to arrhythmias4. In this issue of Nature Cardiovascular Research, Macías et al.5 demonstrate two new mechanisms by which mutations of Kir2.1 may lead to cardiac arrhythmias: (1) formation of a channelosome between Kir2.1 and a major cardiac voltage-gated Na+ channel, Nav1.5, and (2) regulation of the dynamics of Ca2+ release from the intracellular stores by a unique population of Kir2.1 channels, identified in the sarcoplasmic reticulum (Fig. 1).

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Fig. 1: Dual mechanisms of cardiac arrhythmia in the Kir2.1∆314–315 model of Anderson–Tawil syndrome.

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Authors and Affiliations

  1. Department of Kinesiology and Applied Physiology University of Delaware, Newark, DE, USA

    Ibra Fancher

  2. Department of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Irena Levitan

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  1. Ibra Fancher
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  2. Irena Levitan
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Correspondence to Irena Levitan.

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Fancher, I., Levitan, I. Channelosome and intracellular K+ channels in arrhythmia. Nat Cardiovasc Res 1, 874–875 (2022). https://doi.org/10.1038/s44161-022-00143-4

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