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beta-Arrestins bind and decrease cell-surface abundance of the Na+/H+ exchanger NHE5 isoform.

The neuronal Na(+)/H(+) exchanger NHE5 isoform not only resides in the plasma membrane but also accumulates in recycling vesicles by means of clathrin-mediated endocytosis. To further investigate the underlying molecular mechanisms, a human brain cDNA library was screened for proteins that interact with the cytoplasmic C-terminal region of NHE5 by using yeast two-hybrid methodology. One candidate cDNA identified by this procedure encoded beta-arrestin2, a specialized adaptor/scaffolding protein required for internalization and signaling of members of the G protein-coupled receptor superfamily. Direct interaction between the two proteins was demonstrated in vitro by GST fusion protein pull-down assays. Sequences within the N-terminal receptor activation-recognition domain and the C-terminal secondary receptor-binding domain of beta-arrestin2 conferred strong binding to the C terminus of NHE5. Full-length NHE5 and beta-arrestin2 also associated in intact cells, as revealed by their coimmunoprecipitation from extracts of transfected CHO cells. Moreover, ectopic expression of both proteins caused a redistribution of beta-arrestin2 from the cytoplasm to vesicles containing NHE5, and significantly decreased the abundance of the transporter at the cell surface. Comparable results were also obtained for the beta-arrestin1 isoform. These data reveal a broader role for arrestins in the trafficking of integral plasma membrane proteins than previously recognized.

Pubmed ID: 15699339

Authors

  • Szab√≥ EZ
  • Numata M
  • Lukashova V
  • Iannuzzi P
  • Orlowski J

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 22, 2005

Associated Grants

None

Mesh Terms

  • Animals
  • Arrestins
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Humans
  • Membrane Proteins
  • Phosphorylation
  • Protein Isoforms
  • Protein Transport
  • Sodium-Hydrogen Antiporter
  • Transfection