β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from Gs to Gi

Baillie, G. , Sood, A., McPhee, I., Gall, I., Perry, S., Lefkowitz, R. and Houslay, M. (2003) β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from Gs to Gi. Proceedings of the National Academy of Sciences of the United States of America, 100(3), pp. 940-945. (doi:10.1073/pnas.262787199)

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Abstract

Phosphorylation of the β2 adrenoreceptor (β2AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (Gs) to inhibitory guanine nucleotide regulatory protein (Gi). β-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the β2AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the β2AR. In human embryonic kidney 293 cells overexpressing a recombinant β2AR, 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 β2AR 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 β2AR. Rolipram and PDE4D5-D556A also enhance β2AR-mediated activation of extracellular signal-regulated kinases ERK1/2. This is consistent with a switch in coupling of the receptor from Gs to Gi, because the ERK1/2 activation is sensitive to both inhibitors of PKA (H89) and Gi (pertussis toxin). In cardiac myocytes, the β2AR also switches from Gs to Gi 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 β2AR in a physiological system, the cardiac myocyte.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Baillie, Professor George
Authors: Baillie, G., Sood, A., McPhee, I., Gall, I., Perry, S., Lefkowitz, R., and Houslay, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490

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