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Review ArticleReview Article

Regulation of G Protein-Coupled Receptor Function by Na+/H+ Exchange Regulatory Factors

Juan A. Ardura and Peter A. Friedman
Paul A. Insel, ASSOCIATE EDITOR
Pharmacological Reviews December 2011, 63 (4) 882-900; DOI: https://doi.org/10.1124/pr.110.004176
Juan A. Ardura
Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Peter A. Friedman
Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Paul A. Insel
Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Roles: ASSOCIATE EDITOR
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Abstract

Many G protein-coupled receptors (GPCR) exert patterns of cell-specific signaling and function. Mounting evidence now supports the view that cytoplasmic adapter proteins contribute critically to this behavior. Adapter proteins recognize highly conserved motifs such as those for Src homology 3 (SH3), phosphotyrosine-binding (PTB), and postsynaptic density 95/discs-large/zona occludens (PDZ) docking sequences in candidate GPCRs. Here we review the behavior of the Na+/H+ exchange regulatory factor (NHERF) family of PDZ adapter proteins on GPCR signalling, trafficking, and function. Structural determinants of NHERF proteins that allow them to recognize targeted GPCRs are considered. NHERF1 and NHERF2 are capable also of modifying the assembled complex of accessory proteins such as β-arrestins, which have been implicated in regulating GPCR signaling. In addition, NHERF1 and NHERF2 modulate GPCR signaling by altering the G protein to which the receptor binds or affect other regulatory proteins that affect GTPase activity, protein kinase A, phospholipase C, or modify downstream signaling events. Small molecules targeting the site of NHERF1-GPCR interaction are being developed and may become important and selective drug candidates.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.004176.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (4)
Pharmacological Reviews
Vol. 63, Issue 4
1 Dec 2011
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Review ArticleReview Article

NHERF EFFECTS ON GPCR FUNCTION

Juan A. Ardura and Peter A. Friedman
Pharmacological Reviews December 1, 2011, 63 (4) 882-900; DOI: https://doi.org/10.1124/pr.110.004176

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Review ArticleReview Article

NHERF EFFECTS ON GPCR FUNCTION

Juan A. Ardura and Peter A. Friedman
Pharmacological Reviews December 1, 2011, 63 (4) 882-900; DOI: https://doi.org/10.1124/pr.110.004176
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  • Article
    • Abstract
    • I. Introduction: Historical Background and Discovery
    • II. Structure and Structural Determinants of Na+/H+ Exchange Regulatory Factor Proteins
    • III. Tissue, Cell, and Subcellular Localization
    • IV. G Protein-Coupled Receptor Partners and Effects of Na+/H+ Exchange Regulatory Factor-1 on Trafficking and Signaling
    • V. Hormonal Regulation of Na+/H+ Exchange Regulatory Factor-1 Expression
    • VI. Biological Actions of Na+/H+ Exchange Regulatory Factors
    • VII. Post-Translational Modifications
    • VIII. Na+/H+ Exchange Regulatory Factor Mutations and Polymorphisms
    • IX. Conclusions and Future Directions
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • References
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