Pathological activation of CaMKII induces arrhythmogenicity through TRPM4 overactivation

Pflugers Arch. 2021 Mar;473(3):507-519. doi: 10.1007/s00424-020-02507-w. Epub 2021 Jan 4.


TRPM4 is a Ca2+-activated nonselective cation channel involved in cardiovascular physiology and pathophysiology. Based on cellular experiments and numerical simulations, the present study aimed to explore the potential arrhythmogenicity of CaMKII-mediated TRPM4 channel overactivation linked to Ca2+ dysregulation in the heart. The confocal immunofluorescence microscopy, western blot, and proximity ligation assay (PLA) in HL-1 atrial cardiomyocytes and/or TRPM4-expressing TSA201 cells suggested that TRPM4 and CaMKII proteins are closely localized. Co-expression of TRPM4 and CaMKIIδ or a FRET-based sensor Camui in HEK293 cells showed that the extent of TRPM4 channel activation was correlated with that of CaMKII activity, suggesting their functional interaction. Both expressions and interaction of the two proteins were greatly enhanced by angiotensin II treatment, which induced early afterdepolarizations (EADs) at the repolarization phase of action potentials (APs) recorded from HL-1 cells by the current clamp mode of patch clamp technique. This arrhythmic change disappeared after treatment with the TRPM4 channel blocker 9-phenanthrol or CaMKII inhibitor KN-62. In order to quantitatively assess how CaMKII modulates the gating behavior of TRPM4 channel, the ionomycin-permeabilized cell-attached recording was employed to obtain the voltage-dependent parameters such as steady-state open probability and time constants for activation/deactivation at different [Ca2+]i. Numerical simulations incorporating these kinetic data into a modified HL-1 model indicated that > 3-fold increase in TRPM4 current density induces EADs at the late repolarization phase and CaMKII inhibition (by KN-62) completely eliminates them. These results collectively suggest a novel arrhythmogenic mechanism involving excessive CaMKII activity that causes TRPM4 overactivation in the stressed heart.

Keywords: Arrhythmogenicity; Ca dynamics; Simulation; TRP channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrhythmias, Cardiac / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cell Line
  • Humans
  • Models, Theoretical
  • Myocytes, Cardiac / metabolism*
  • TRPM Cation Channels / metabolism*


  • TRPM Cation Channels
  • TRPM4 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2