Role of receptor kinase in long-term desensitization of the cardiac muscarinic receptor-K+ channel system

Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H819-28. doi: 10.1152/ajpheart.00515.2001.

Abstract

Desensitization of the cardiac muscarinic K+ channel was studied in cultured neonatal rat atrial cells and in Chinese hamster ovary (CHO) cells transfected with muscarinic receptor (HM(2)), G protein-coupled inward rectifying K+ channels 1 and 4, and G protein-coupled receptor kinase 2. In atrial cells incubated in 10 microM carbachol for 24 h, channel activity in cell-attached patches was substantially reduced as a result of long-term desensitization. The long-term desensitization was also observed in CHO cells transfected with the wild-type receptor and receptor kinase (as well as the channel). However, long-term desensitization was greatly reduced or abolished if the cells were 1) not transfected with the receptor kinase, 2) transfected with a mutant receptor lacking phosphorylation sites (rather than the wild-type receptor), or 3) transfected with a mutant receptor kinase lacking kinase activity (rather than the wild-type receptor kinase). We suggest that long-term desensitization of the cardiac muscarinic receptor-K+ channel system to muscarinic agonist may involve phosphorylation of the receptor by receptor kinase.

MeSH terms

  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Electrophysiology
  • G-Protein-Coupled Receptor Kinase 2
  • Mutation
  • Myocardium / metabolism*
  • Phosphorylation
  • Potassium Channels / metabolism*
  • Rats
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism*
  • Time Factors
  • Transfection
  • beta-Adrenergic Receptor Kinases

Substances

  • Potassium Channels
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • Receptor Protein-Tyrosine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Grk2 protein, rat
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 2