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• W1982446007 abstract "Phosphorylation by protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs) desensitize β 2 -adrenergic receptor (β 2 AR) signaling, and these are thought to be mechanisms involved with cell and organ homeostasis and tolerance to agonists. However, there is little direct evidence that these events are relevant to β 2 AR physiological function, such as airway smooth muscle (ASM) relaxation leading to bronchodilation. To maintain cell- and receptor-specificity without altering the natural complement of kinases/arrestins, transgenic mice were generated expressing the human WT and mutated β 2 ARs lacking PKA and/or GRK phosphorylation sites on ASM at ≈4-fold over background. Functional gains in response to β-agonist from the selective loss of these mechanisms were determined in mouse airways. Relaxation kinetics were altered in all mutant airways compared with β 2 WT. At low receptor occupancy, β 2 PKA(-) had enhanced agonist-promoted relaxation, while β 2 GRK(-) airways were unaffected. In contrast, at saturating agonist concentrations, the greatest relaxation enhancement was with β 2 GRK(-), with no evidence for additivity when PKA sites were also removed. For the full range of responses, the β 2 PKA(-)/GRK(-) airways had the greatest relaxation efficiency, indicating a graded effect of GRKs as agonist concentration increased. ASM cAMP levels paralleled relaxation phenotypes. No interaction between PKA phosphorylation of β 2 AR and GRK-promoted events was identified by β-arrestin-2 recruitment. Thus, these two mechanisms indeed impact a relevant β 2 AR physiologic function, acting as attenuators of the acute response, and represent specific interfaces where adjunct therapy or biased ligands may improve β-agonist treatment of obstructive lung disease." @default.
• W1982446007 created "2016-06-24" @default.
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• W1982446007 date "2009-09-01" @default.
• W1982446007 modified "2023-09-26" @default.
• W1982446007 title "Targeted transgenesis reveals discrete attenuator functions of GRK and PKA in airway β ₂ -adrenergic receptor physiologic signaling" @default.
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• W1982446007 doi "https://doi.org/10.1073/pnas.0906034106" @default.
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