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Beta(2)-adrenergic receptor down-regulation - evidence for a pathway that does not require endocytosis

Academic Article
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Overview

authors

  • Jockers, R.
  • Angers, S.
  • Da Silva, A.
  • Benaroch, P.
  • Strosberg, Donny
  • Bouvier, M.
  • Marullo, S.

publication date

  • October 1999

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Sustained activation of most G protein-coupled receptors causes a time-dependent reduction of receptor density in intact cells. This phenomenon, known as down-regulation, is believed to depend on a ligand-promoted change of receptor sorting from the default endosome-plasma membrane recycling pathway to the endosome-lysosome degradation pathway. This model is based on previous studies of epidermal growth factor (EGF) receptor degradation and implies that receptors need to be endocytosed to be down-regulated. In stable clones of L cells expressing beta(2)-adrenergic receptors (beta(2)ARs), sustained agonist treatment caused a time-dependant decrease in both beta(2)AR binding sites and immuno-detectable receptor. Blocking beta(2)AR endocytosis with chemical treatments or by expressing a dominant negative mutant of dynamin could not prevent this phenomenon. Specific blockers of the two main intracellular degradation pathways, lysosomal and proteasome-associated, were ineffective in preventing beta(2)AR down-regulation. Further evidence for an endocytosis-independent pathway of beta(2)AR down-regulation was provided by studies in A431 cells, a cell line expressing both endogenous beta(2)AR and EGF receptors. In these cells, inhibition of endocytosis and inactivation of the lysosomal degradation pathway did not block beta(2)AR down-regulation, whereas EGF degradation was inhibited. These data indicate that, contrary to what is currently postulated, receptor endocytosis is not a necessary prerequisite for beta(2)AR down-regulation and that the inactivation of beta(2)ARs, leading to a reduction in binding sites, may occur at the plasma membrane.

subject areas

  • Adrenergic beta-2 Receptor Agonists
  • Animals
  • Binding Sites
  • Cell Line
  • Cell Membrane
  • Cysteine Endopeptidases
  • Down-Regulation
  • Dynamins
  • Endocytosis
  • Epidermal Growth Factor
  • GTP Phosphohydrolases
  • Gene Expression
  • Humans
  • Isoproterenol
  • L Cells (Cell Line)
  • Lysosomes
  • Mice
  • Microscopy, Fluorescence
  • Multienzyme Complexes
  • Proteasome Endopeptidase Complex
  • Receptors, Adrenergic, beta-2
  • Recombinant Fusion Proteins
  • Serine Proteinase Inhibitors
  • Ubiquitins
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.274.41.28900

PubMed ID

  • 10506134
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Additional Document Info

start page

  • 28900

end page

  • 28908

volume

  • 274

issue

  • 41

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