Overexpression of M₃ muscarinic receptor is a novel strategy for preventing sudden cardiac death in transgenic mice

Mol Med. 2011;17(11-12):1179-87. doi: 10.2119/molmed.2011.00093. Epub 2011 Jul 13.


The present study was designed to investigate the cardiac benefits of M₃ muscarinic receptor (M₃-mAChR) overexpression and whether these effects are related to the regulation of the inward rectifying K⁺ channel by microRNA-1 (miR-1) in a conditional overexpression mouse model. A cardiac-specific M₃-mAChR transgenic mouse model was successfully established for the first time in this study using microinjection, and the overexpression was confirmed by both reverse transcriptase-polymerase chain reaction and Western blot techniques. We demonstrated that M₃-mAChR overexpression dramatically reduced the incidence of arrhythmias and decreased the mortality in a mouse model of myocardial ischemia-reperfusion (I/R). By using whole-cell patch techniques, M₃-mAChR overexpression significantly shortened the action potential duration and restored the membrane repolarization by increasing the inward rectifying K⁺ current. By using Western blot techniques, M₃-mAChR overexpression also rescued the expression of the inward rectifying K⁺ channel subunit Kir2.1 after myocardial I/R injury. This result was accompanied by suppression of upregulation miR-1. We conclude that M₃-mAChR overexpression reduced the incidence of arrhythmias and mortality after myocardial I/R by protecting the myocardium from ischemia in mice. This effect may be mediated by increasing the inward rectifying K⁺ current by downregulation of arrhythmogenic miR-1 expression, which might partially be a novel strategy for antiarrhythmias, leading to sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitine
  • Action Potentials
  • Animals
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Death, Sudden, Cardiac / prevention & control*
  • Gene Expression Regulation
  • Heart Ventricles / pathology
  • Ion Channel Gating
  • Mice
  • Mice, Transgenic
  • MicroRNAs / metabolism
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myosin Heavy Chains / genetics
  • Patch-Clamp Techniques
  • Potassium Channels / genetics
  • Potassium Channels / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Muscarinic M3 / genetics
  • Receptor, Muscarinic M3 / metabolism*


  • Calcium Channels
  • MicroRNAs
  • Mirn1 microRNA, mouse
  • Potassium Channels
  • Protein Subunits
  • RNA, Messenger
  • Receptor, Muscarinic M3
  • Myosin Heavy Chains
  • Aconitine