Beta-Arrestins Bind and Decrease Cell-surface Abundance of the Na+/H+ Exchanger NHE5 Isoform

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Feb 9

PMID 15699339

Citations 21

Authors

Elod Z Szabo

Masayuki Numata

Viktoria Lukashova

Pietro Iannuzzi

John Orlowski

Affiliations

Soon will be listed here.

Abstract

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.

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