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Review ArticleMinireview

Adhesion G Protein-Coupled Receptors: Signaling, Pharmacology, and Mechanisms of Activation

Kevin J. Paavola and Randy A. Hall
Molecular Pharmacology November 2012, 82 (5) 777-783; DOI: https://doi.org/10.1124/mol.112.080309
Kevin J. Paavola
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
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Randy A. Hall
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
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Abstract

The adhesion G protein-coupled receptors (GPCRs) are a distinct family of more than 30 receptors in vertebrate genomes. These receptors have been shown to play pivotal roles in a diverse range of biological functions and are characterized by extremely large N termini featuring various adhesion domains capable of mediating cell-cell and cell-matrix interactions. The adhesion GPCR N termini also contain GPCR proteolytic site motifs that undergo autocatalytic cleavage during receptor processing to create mature GPCRs existing as noncovalently attached complexes between the N terminus and transmembrane regions. There is mounting evidence that adhesion GPCRs can couple to G proteins to activate a variety of different downstream signaling pathways. Furthermore, recent studies have demonstrated that adhesion GPCR N termini can bind to multiple ligands, which may differentially activate receptor signaling and/or mediate cell adhesion. In addition, studies on several distinct adhesion GPCRs have revealed that truncations of the N termini result in constitutively active receptors, suggesting a model of receptor activation in which removal of the N terminus may be a key event in stimulating receptor signaling. Because mutations to certain adhesion GPCRs cause human disease and because many members of this receptor family exhibit highly discrete distribution patterns in different tissues, the adhesion GPCRs represent a class of potentially important drug targets that have not yet been exploited. For this reason, understanding the mechanisms of activation for these receptors and elucidating their downstream signaling pathways can provide insights with the potential to lead to novel therapeutic agents.

Footnotes

  • The work is supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS072394].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.080309.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    7TM
    seven-transmembrane
    GPS
    GPCR proteolytic site
    GAIN
    GPCR autoproteolysis-inducing
    HEK
    human embryonic kidney
    EMR2
    EGF-like module-containing mucin-like hormone receptor-like 2
    LTX
    latrotoxin
    SRE
    serum response element
    BAI
    brain-specific angiogenesis inhibitor
    NFAT
    nuclear factor of activated T-cells
    FLRT
    fibronectin leucine-rich repeat transmembrane
    TG2
    transglutaminase 2
    PAR
    protease-activated receptor.

  • Received May 30, 2012.
  • Accepted July 20, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Review ArticleMinireview

Adhesion G Protein-Coupled Receptor Signaling

Kevin J. Paavola and Randy A. Hall
Molecular Pharmacology November 1, 2012, 82 (5) 777-783; DOI: https://doi.org/10.1124/mol.112.080309

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Review ArticleMinireview

Adhesion G Protein-Coupled Receptor Signaling

Kevin J. Paavola and Randy A. Hall
Molecular Pharmacology November 1, 2012, 82 (5) 777-783; DOI: https://doi.org/10.1124/mol.112.080309
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  • Article
    • Abstract
    • Introduction
    • Adhesion GPCR Signaling through G Proteins
    • Importance of the N Terminus for Adhesion GPCR Signaling
    • Potential Ligands for Adhesion GPCRs
    • Conclusions and Future Directions
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