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

Publication ,  Journal Article
Baillie, GS; Sood, A; McPhee, I; Gall, I; Perry, SJ; Lefkowitz, RJ; Houslay, MD
Published in: Proc Natl Acad Sci U S A
February 4, 2003

Phosphorylation of the beta(2) adrenoreceptor (beta(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)). beta-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the beta(2)AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the beta(2)AR. In human embryonic kidney 293 cells overexpressing a recombinant beta(2)AR, stimulation with isoprenaline recruits beta-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 beta(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 beta(2)AR. Rolipram and PDE4D5-D556A also enhance beta(2)AR-mediated activation of extracellular signal-regulated kinases ERK12. This is consistent with a switch in coupling of the receptor from G(s) to G(i), because the ERK12 activation is sensitive to both inhibitors of PKA (H89) and G(i) (pertussis toxin). In cardiac myocytes, the beta(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 ERK12. Rolipram robustly enhances this activation in a manner sensitive to both pertussis toxin and H89. Adenovirus-mediated expression of PDE4D5-D556A also potentiates ERK12 activation. Thus, receptor-stimulated beta-arrestin-mediated recruitment of PDE4 plays a central role in the regulation of G protein switching by the beta(2)AR in a physiological system, the cardiac myocyte.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 4, 2003

Volume

100

Issue

3

Start / End Page

940 / 945

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transfection
  • Time Factors
  • Sulfonamides
  • Signal Transduction
  • Rolipram
  • Receptors, Adrenergic, beta
  • Rats
  • Phosphorylation
  • Phosphoric Diester Hydrolases
 

Citation

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Baillie, G. S., Sood, A., McPhee, I., Gall, I., Perry, S. J., Lefkowitz, R. J., & Houslay, M. D. (2003). beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A, 100(3), 940–945. https://doi.org/10.1073/pnas.262787199
Baillie, George S., Arvind Sood, Ian McPhee, Irene Gall, Stephen J. Perry, Robert J. Lefkowitz, and Miles D. Houslay. “beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi.Proc Natl Acad Sci U S A 100, no. 3 (February 4, 2003): 940–45. https://doi.org/10.1073/pnas.262787199.
Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, et al. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):940–5.
Baillie, George S., et al. “beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi.Proc Natl Acad Sci U S A, vol. 100, no. 3, Feb. 2003, pp. 940–45. Pubmed, doi:10.1073/pnas.262787199.
Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):940–945.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 4, 2003

Volume

100

Issue

3

Start / End Page

940 / 945

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transfection
  • Time Factors
  • Sulfonamides
  • Signal Transduction
  • Rolipram
  • Receptors, Adrenergic, beta
  • Rats
  • Phosphorylation
  • Phosphoric Diester Hydrolases