Differential subunit composition of the G protein-activated inward-rectifier potassium channel during cardiac development

J Clin Invest. 2004 Oct;114(7):994-1001. doi: 10.1172/JCI15925.


Parasympathetic slowing of the heart rate is predominantly mediated by acetylcholine-dependent activation of the G protein-gated potassium (K+) channel (IK,ACh). This channel is composed of 2 inward-rectifier K+ (Kir) channel subunits, Kir3.1 and Kir3.4, that display distinct functional properties. Here we show that subunit composition of IK,ACh changes during embryonic development. At early stages, IK,ACh is primarily formed by Kir3.1, while in late embryonic and adult cells, Kir3.4 is the predominant subunit. This change in subunit composition results in reduced rectification of IK,ACh, allowing for marked K+ currents over the whole physiological voltage range. As a consequence, IK,ACh is able to generate the membrane hyperpolarization that underlies the strong negative chronotropy occurring in late- but not early-stage atrial cardiomyocytes upon application of muscarinic agonists. Both strong negative chronotropy and membrane hyperpolarization can be induced in early-stage cardiomyocytes by viral overexpression of the mildly rectifying Kir3.4 subunit. Thus, a switch in subunit composition is used to adopt IK,ACh to its functional role in adult cardiomyocytes.

MeSH terms

  • Acetylcholine / metabolism
  • Action Potentials / physiology
  • Animals
  • Bee Venoms / pharmacology
  • Carbachol / pharmacology
  • Cells, Cultured
  • Cholinergic Agonists / pharmacology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • GTP-Binding Proteins / metabolism*
  • Heart / drug effects
  • Heart / embryology*
  • Heart / growth & development*
  • Heart Rate / drug effects
  • Mice
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Receptor, Muscarinic M2 / metabolism
  • Recombinant Proteins / metabolism
  • Vasodilator Agents / metabolism


  • Bee Venoms
  • Cholinergic Agonists
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Kcnj3 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • Protein Subunits
  • Receptor, Muscarinic M2
  • Recombinant Proteins
  • Vasodilator Agents
  • tertiapin
  • Carbachol
  • GTP-Binding Proteins
  • Acetylcholine