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• W2109771867 abstract "Phosphorylation of the β 2 adrenoreceptor (β 2 AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (G s ) to inhibitory guanine nucleotide regulatory protein (G i ). β-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the β 2 AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the β 2 AR. In human embryonic kidney 293 cells overexpressing a recombinant β 2 AR, stimulation with isoprenaline recruits β-arrestins 1 and 2 as well as both PDE4D3 and PDE4D5 to the receptor and stimulates receptor phosphorylation by PKA. The PKA phosphorylation status of the β 2 AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the β 2 AR. Rolipram and PDE4D5-D556A also enhance β 2 AR-mediated activation of extracellular signal-regulated kinases ERK1/2. This is consistent with a switch in coupling of the receptor from G s to G i , because the ERK1/2 activation is sensitive to both inhibitors of PKA (H89) and G i (pertussis toxin). In cardiac myocytes, the β 2 AR also switches from G s to G i coupling. Treating primary cardiac myocytes with isoprenaline induces recruitment of PDE4D3 and PDE4D5 to membranes and activates ERK1/2. Rolipram robustly enhances this activation in a manner sensitive to both pertussis toxin and H89. Adenovirus-mediated expression of PDE4D5-D556A also potentiates ERK1/2 activation. Thus, receptor-stimulated β-arrestin-mediated recruitment of PDE4 plays a central role in the regulation of G protein switching by the β 2 AR in a physiological system, the cardiac myocyte." @default.
• W2109771867 created "2016-06-24" @default.
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• W2109771867 date "2003-01-27" @default.
• W2109771867 modified "2023-10-16" @default.
• W2109771867 title "β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from G _s to G _i" @default.
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• W2109771867 doi "https://doi.org/10.1073/pnas.262787199" @default.
• W2109771867 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/298705" @default.
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