Phosphodiesterase-4 gates the ability of protein kinase A to phosphorylate G-protein receptor kinase-2 and influence its translocation.

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  • Author(s): Houslay MD;Houslay MD; Baillie GS
  • Source:
    Biochemical Society transactions [Biochem Soc Trans] 2006 Aug; Vol. 34 (Pt 4), pp. 474-5.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Portland Press On The Behalf Of The Biochemical Society Country of Publication: England NLM ID: 7506897 Publication Model: Print Cited Medium: Print ISSN: 0300-5127 (Print) Linking ISSN: 03005127 NLM ISO Abbreviation: Biochem Soc Trans Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Portland Press On The Behalf Of The Biochemical Society
    • Subject Terms:
      3',5'-Cyclic-AMP Phosphodiesterases/*metabolism ; Cyclic AMP-Dependent Protein Kinases/*metabolism ; Protein Serine-Threonine Kinases/*metabolism; 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Humans ; Muscle Cells/enzymology ; Phosphorylation ; Protein Transport
    • Abstract:
      Challenge of the beta(2)Ar (beta(2)-adrenergic receptor) with isoprenaline in HEK-293beta(2) cells (human embryonic kidney cells stably overexpressing a FLAG- and green fluorescent protein-tagged beta(2)Ar) results in the PKA (cAMP-dependent protein kinase) phosphorylation of GRK2 (G-protein receptor kinase-2). This response was enhanced when PDE4 (phosphodiesterase-4) activity was attenuated using either rolipram, a PDE4-selective inhibitor, or with siRNA (small interfering RNA) knockdown of both PDE4B and PDE4D. Rolipram also facilitated GRK2 recruitment to the membrane and phosphorylation of the beta(2)Ar by GRK2 in response to isoprenaline challenge of cells. In resting cells, rolipram treatment alone is sufficient to promote PKA phosphorylation of GRK2, with consequential effects on GRK2 translocation and GRK2 phosphorylation of the beta(2)Ar. Similar effects are observed in cardiac myocytes. We propose that PDE4 activity protects GRK2 from inappropriate phosphorylation by PKA in resting cells that might have occurred through fluctuations in basal cAMP levels. Thus PDE4 gates the action of PKA to phosphorylate GRK2.
    • Grant Information:
      G8604010 United Kingdom MRC_ Medical Research Council
    • Accession Number:
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
      EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
      EC 3.1.4.17 (PDE4B protein, human)
      EC 3.1.4.17 (PDE4D protein, human)
    • Publication Date:
      Date Created: 20060722 Date Completed: 20060914 Latest Revision: 20220129
    • Publication Date:
      20221213
    • Accession Number:
      10.1042/BST0340474
    • Accession Number:
      16856836