Inhibitory G-protein-mediated modulation of slow delayed rectifier potassium channels contributes to increased susceptibility to arrhythmogenesis in aging heart

Heart Rhythm. 2021 Dec;18(12):2197-2209. doi: 10.1016/j.hrthm.2021.09.014. Epub 2021 Sep 15.

Abstract

Background: Slow delayed rectifier potassium current (IKs) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of IKs and its involvement in age-dependent arrhythmogenesis.

Objective: The purpose of this study was to investigate age-related alteration of the IKs response to β-adrenergic receptor (βAR) activation.

Methods: Dunkin-Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K+ currents. Optical mapping of membrane potential was performed in ex vivo heart.

Results: There was no difference in IKs density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to IKs potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on IKs in a concentration-dependent manner in old guinea pig hearts. The β2AR antagonist, but not β1AR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells cotransfected with cloned IKs channel and β2AR, ISO enhanced the current but reduced it when cells were cotransfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, Gβγ inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of IKs by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias.

Conclusion: βAR activation acutely induces an inhibitory IKs response in aging guinea pig hearts through β2AR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.

Keywords: Aging; Arrhythmias; Delayed rectifier K(+) current; Inhibitory G protein; β-Adrenoceptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Antagonists / pharmacology
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Arrhythmias, Cardiac / metabolism*
  • Cellular Senescence / physiology*
  • Delayed Rectifier Potassium Channels / metabolism*
  • GTP-Binding Protein alpha Subunits, Gi-Go / antagonists & inhibitors
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Isoproterenol / pharmacology
  • Membrane Potentials* / drug effects
  • Membrane Potentials* / physiology
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / metabolism
  • Patch-Clamp Techniques / methods
  • Pertussis Toxin / pharmacology

Substances

  • Adrenergic beta-2 Receptor Antagonists
  • Anti-Arrhythmia Agents
  • Delayed Rectifier Potassium Channels
  • Pertussis Toxin
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Isoproterenol