Kir2.1-NaV1.5 channelosome and its role in arrhythmias in inheritable cardiac diseases

Heart Rhythm. 2024 May;21(5):630-646. doi: 10.1016/j.hrthm.2024.01.017. Epub 2024 Jan 18.

Abstract

Sudden cardiac death in children and young adults is a relatively rare but tragic event whose pathophysiology is unknown at the molecular level. Evidence indicates that the main cardiac sodium channel (NaV1.5) and the strong inward rectifier potassium channel (Kir2.1) physically interact and form macromolecular complexes (channelosomes) with common partners, including adapter, scaffolding, and regulatory proteins that help them traffic together to their eventual membrane microdomains. Most important, dysfunction of either or both ion channels has direct links to hereditary human diseases. For example, certain mutations in the KCNJ2 gene encoding the Kir2.1 protein result in Andersen-Tawil syndrome type 1 and alter both inward rectifier potassium and sodium inward currents. Similarly, trafficking-deficient mutations in the gene encoding the NaV1.5 protein (SCN5A) result in Brugada syndrome and may also disturb both inward rectifier potassium and sodium inward currents. Moreover, gain-of-function mutations in KCNJ2 result in short QT syndrome type 3, which is extremely rare but highly arrhythmogenic, and can modify Kir2.1-NaV1.5 interactions in a mutation-specific way, further highlighting the relevance of channelosomes in ion channel diseases. By expressing mutant proteins that interrupt or modify Kir2.1 or NaV1.5 function in animal models and patient-specific pluripotent stem cell-derived cardiomyocytes, investigators are defining for the first time the mechanistic framework of how mutation-induced dysregulation of the Kir2.1-NaV1.5 channelosome affects cardiac excitability, resulting in arrhythmias and sudden death in different cardiac diseases.

Keywords: Arrhythmogenic mechanisms; Channelopathies; Ion channels; Macromolecular complexes; Sudden cardiac death.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arrhythmias, Cardiac* / genetics
  • Arrhythmias, Cardiac* / metabolism
  • Arrhythmias, Cardiac* / physiopathology
  • Humans
  • Mutation
  • NAV1.5 Voltage-Gated Sodium Channel* / genetics
  • NAV1.5 Voltage-Gated Sodium Channel* / metabolism
  • Potassium Channels, Inwardly Rectifying* / genetics
  • Potassium Channels, Inwardly Rectifying* / metabolism

Substances

  • Potassium Channels, Inwardly Rectifying
  • NAV1.5 Voltage-Gated Sodium Channel
  • Kir2.1 channel
  • KCNJ2 protein, human