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Molecular mechanisms of G protein-coupled receptor desensitization and resensitization.

Publication ,  Journal Article
Ferguson, SS; Zhang, J; Barak, LS; Caron, MG
Published in: Life Sci
1998

Beta-arrestin proteins play a dual role in regulating G protein-coupled receptor (GPCR) responsiveness by contributing to both receptor desensitization and internalization. Recently, beta-arrestins were also shown to be critical determinants for beta2-adrenergic receptor (beta2AR) resensitization. This was demonstrated by overexpressing wild-type beta-arrestins to rescue the resensitization-defect of a beta2AR (Y326A) mutant (gain of function) and overexpressing a dominant-negative beta-arrestin inhibitor of beta2AR sequestration to impair beta2AR dephosphorylation and resensitization (loss of function). Moreover, the ability of the beta2AR to resensitize in different cell types was shown to be dependent upon beta-arrestin expression levels. To further study the mechanisms underlying beta-arrestin function, green fluorescent protein was coupled to beta-arrestin2 (beta arr2GFP), thus allowing the real-time visualization of the agonist-dependent trafficking of beta-arrestin in living cells. Beta arr2GFP translocation from the cytoplasm to the plasma membrane proceeded with a time course, sensitivity and specificity that was indistinguishable from the most sensitive second messenger readout systems. Beta arr2GFP translocation was GRK-dependent and was demonstrated for 16 different ligand-activated GPCRs. Because beta-arrestin binding is a common divergent step in GPCR signalling, this assay represents a universal methodology for screening orphan receptors, GRK inhibitors and novel GPCR ligands. Moreover, beta arr2GFP provides a valuable new tool to dissect the biological function and regulation of beta-arrestin proteins.

Duke Scholars

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Published In

Life Sci

DOI

ISSN

0024-3205

Publication Date

1998

Volume

62

Issue

17-18

Start / End Page

1561 / 1565

Location

Netherlands

Related Subject Headings

  • beta-Arrestins
  • Sensitivity and Specificity
  • Receptors, Cell Surface
  • Pharmacology & Pharmacy
  • GTP-Binding Proteins
  • Endocytosis
  • Arrestins
  • Animals
  • 3214 Pharmacology and pharmaceutical sciences
  • 3101 Biochemistry and cell biology
 

Citation

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Ferguson, S. S., Zhang, J., Barak, L. S., & Caron, M. G. (1998). Molecular mechanisms of G protein-coupled receptor desensitization and resensitization. Life Sci, 62(17–18), 1561–1565. https://doi.org/10.1016/s0024-3205(98)00107-6
Ferguson, S. S., J. Zhang, L. S. Barak, and M. G. Caron. “Molecular mechanisms of G protein-coupled receptor desensitization and resensitization.Life Sci 62, no. 17–18 (1998): 1561–65. https://doi.org/10.1016/s0024-3205(98)00107-6.
Ferguson SS, Zhang J, Barak LS, Caron MG. Molecular mechanisms of G protein-coupled receptor desensitization and resensitization. Life Sci. 1998;62(17–18):1561–5.
Ferguson, S. S., et al. “Molecular mechanisms of G protein-coupled receptor desensitization and resensitization.Life Sci, vol. 62, no. 17–18, 1998, pp. 1561–65. Pubmed, doi:10.1016/s0024-3205(98)00107-6.
Ferguson SS, Zhang J, Barak LS, Caron MG. Molecular mechanisms of G protein-coupled receptor desensitization and resensitization. Life Sci. 1998;62(17–18):1561–1565.
Journal cover image

Published In

Life Sci

DOI

ISSN

0024-3205

Publication Date

1998

Volume

62

Issue

17-18

Start / End Page

1561 / 1565

Location

Netherlands

Related Subject Headings

  • beta-Arrestins
  • Sensitivity and Specificity
  • Receptors, Cell Surface
  • Pharmacology & Pharmacy
  • GTP-Binding Proteins
  • Endocytosis
  • Arrestins
  • Animals
  • 3214 Pharmacology and pharmaceutical sciences
  • 3101 Biochemistry and cell biology