Beta-adrenergic receptor kinase-1 acutely regulates PTH/PTHrP receptor signalling in human osteoblastlike cells.
To investigate whether G protein-coupled receptor kinases (GRKs) are involved in the regulation of the PTH/PTHrPR, we have established mutant SaOS-2 cells which stably overexpress (> 10-20-fold) a dominant negative form of the beta-adrenergic receptor kinase-1 (beta ARK-1). Acute (< or = 2 h) incubation with hPTH (1-34) induced significantly less (by up to 50%) downregulation of the PTH/PTHrPR in beta ARK-1 mutant SaOS-2 cells than observed in wild-type cells. Pretreatment of wild-type cells with PTH for 2 h induced homologous cAMP desensitisation to a second challenge with PTH, while the effect was blunted by up to 60% in beta ARK-1 mutant cells. We conclude that activation of beta ARK-1 (or a closely related GRK) is a critical component of the acute phase (< or = 2 h) of PTH-induced receptor downregulation and homologous cAMP desensitisation of the PTH/PTHrPR.
Fukayama
S
S
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA, USA. sfukayam@hsph.harvard.edu
Kong
G
G
Benovic
J L
JL
Meurer
E
E
Tashjian
A H
AH
D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D009154:Mutation / Q000502:physiology; D015513:Oncogene Proteins; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000502:physiology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases; D000094963:Axl Receptor Tyrosine Kinase
D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D005576:Colforsin; D000242:Cyclic AMP; D020794:Receptor Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human