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Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways.


Norepinephrine released by the sympathetic nerve terminals regulates the immune system primarily via its stimulation of beta(2)-adrenergic receptor (beta(2)AR), but the underlying molecular mechanisms remain to be elicited. Beta(2)AR, a well-studied G protein-coupled receptor (GPCR), is functionally regulated by beta-arrestin2, which not only causes receptor desensitization and internalization but also serves as a signaling molecule in GPCR signal transduction. Here we show that beta-arrestin2 directly interacts with IkappaBalpha (inhibitor of NF-kappaB, the key molecule in innate and adaptive immunity) and thus prevents the phosphorylation and degradation of IkappaBalpha. Consequently, beta-arrestin2 effectively modulates activation of NF-kappaB and expression of NF-kappaB target genes. Moreover, stimulation of beta(2)AR significantly enhances beta-arrestin2-IkappaBalpha interaction and greatly promotes beta-arrestin2 stabilization of IkappaBalpha, indicating that beta-arrestin2 mediates a crosstalk between beta(2)AR and NF-kappaB signaling pathways. Taken together, the current study may present a novel mechanism for regulation of the immune system by the sympathetic nervous system.

Pubmed ID: 15125834


  • Gao H
  • Sun Y
  • Wu Y
  • Luan B
  • Wang Y
  • Qu B
  • Pei G


Molecular cell

Publication Data

May 7, 2004

Associated Grants


Mesh Terms

  • Arrestins
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • I-kappa B Proteins
  • Mutation
  • NF-kappa B
  • Neuroimmunomodulation
  • Phosphorylation
  • Protein Structure, Tertiary
  • Receptors, Adrenergic, beta-2
  • Receptors, G-Protein-Coupled
  • Signal Transduction
  • Sympathetic Nervous System