Role of receptor kinase in long-term desensitization of the cardiac muscarinic receptor-K+ channel system.
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.
Shui
Z
Z
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Khan
I A
IA
Tsuga
H
H
Dobrzynski
H
H
Haga
T
T
Henderson
Z
Z
Boyett
M R
MR
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004594:Electrophysiology; D054769:G-Protein-Coupled Receptor Kinase 2; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases
D015221:Potassium Channels; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D020794:Receptor Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2