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Research ArticleArticle

Ligand Bias at Metabotropic Glutamate 1a Receptors: Molecular Determinants That Distinguish β-Arrestin-Mediated from G Protein-Mediated Signaling

Andrew C. Emery, John O. DiRaddo, Eric Miller, Hannah A. Hathaway, Sergey Pshenichkin, Guy Rodrigue Takoudjou, Ewa Grajkowska, Robert P. Yasuda, Barry B. Wolfe and Jarda T. Wroblewski
Molecular Pharmacology August 2012, 82 (2) 291-301; DOI: https://doi.org/10.1124/mol.112.078444
Andrew C. Emery
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John O. DiRaddo
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Eric Miller
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Hannah A. Hathaway
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Sergey Pshenichkin
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Guy Rodrigue Takoudjou
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Ewa Grajkowska
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Robert P. Yasuda
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Barry B. Wolfe
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Jarda T. Wroblewski
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Abstract

The metabotropic glutamate 1a (mGlu1a) receptor is a G protein-coupled receptor linked with phosphoinositide (PI) hydrolysis and with β-arrestin-1-mediated sustained extracellular signal-regulated kinase (ERK) phosphorylation and cytoprotective signaling. Previously, we reported the existence of ligand bias at this receptor, inasmuch as glutamate induced both effects, whereas quisqualate induced only PI hydrolysis. In the current study, we showed that mGlu1 receptor agonists such as glutamate, aspartate, and l-cysteate were unbiased and activated both signaling pathways, whereas quisqualate and (S)-3,5-dihydroxyphenylglycine stimulated only PI hydrolysis. Competitive antagonists inhibited only PI hydrolysis and not the β-arrestin-dependent pathway, whereas a noncompetitive mGlu1 receptor antagonist blocked both pathways. Mutational analysis of the ligand binding domain of the mGlu1a receptor revealed that Thr188 residues were essential for PI hydrolysis but not for protective signaling, whereas Arg323 and Lys409 residues were required for β-arrestin-1-mediated sustained ERK phosphorylation and cytoprotective signaling but not for PI hydrolysis. Therefore, the mechanism of ligand bias appears to involve different modes of agonist interactions with the receptor ligand binding domain. Although some mGlu1a receptor agonists are biased toward PI hydrolysis, we identified two endogenous compounds, glutaric acid and succinic acid, as new mGlu1 receptor agonists that are fully biased toward β-arrestin-mediated protective signaling. Pharmacological studies indicated that, in producing the two effects, glutamate interacted in two distinct ways with mGlu1 receptors, inasmuch as competitive mGlu1 receptor antagonists that blocked PI hydrolysis did not inhibit cytoprotective signaling. Quisqualate, which is biased toward PI hydrolysis, failed to inhibit glutamate-induced protection, and glutaric acid, which is biased toward protection, did not interfere with glutamate-induced PI hydrolysis. Taken together, these data indicate that ligand bias at mGlu1 receptors is attributable to different modes of receptor-glutamate interactions, which are differentially coupled to PI hydrolysis and β-arrestin-mediated cytoprotective signaling, and they reveal the existence of new endogenous agonists acting at mGlu1 receptors.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS37436, NS041218] (the latter to A.C.E.).

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

    http://dx.doi.org/10.1124/mol.112.078444.

  • ABBREVIATIONS:

    mGlu
    metabotropic glutamate
    DHPG
    (S)-3,5-dihydroxyphenylglycine
    HRP
    horseradish peroxidase
    CHO
    Chinese hamster ovary
    GPCR
    G protein-coupled receptor
    LY367385
    (+)-2-methyl-4-carboxyphenyl-glycine
    shRNA
    short hairpin RNA
    ERK
    extracellular signal-regulated kinase
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    PI
    phosphoinositide
    PLC
    phospholipase C
    U73122
    1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione
    3-MATIDA
    α-amino-5-carboxy-3-methyl-2-thiopheneacetic acid
    YM298198
    6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide hydrochloride
    PBS
    phosphate-buffered saline
    PBST
    phosphate-buffered saline/0.1% Triton X-100
    JNJ16259685
    (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone.

  • Received February 22, 2012.
  • Accepted May 10, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (2)
Molecular Pharmacology
Vol. 82, Issue 2
1 Aug 2012
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Research ArticleArticle

Ligand Bias at mGlu1a Receptors

Andrew C. Emery, John O. DiRaddo, Eric Miller, Hannah A. Hathaway, Sergey Pshenichkin, Guy Rodrigue Takoudjou, Ewa Grajkowska, Robert P. Yasuda, Barry B. Wolfe and Jarda T. Wroblewski
Molecular Pharmacology August 1, 2012, 82 (2) 291-301; DOI: https://doi.org/10.1124/mol.112.078444

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Research ArticleArticle

Ligand Bias at mGlu1a Receptors

Andrew C. Emery, John O. DiRaddo, Eric Miller, Hannah A. Hathaway, Sergey Pshenichkin, Guy Rodrigue Takoudjou, Ewa Grajkowska, Robert P. Yasuda, Barry B. Wolfe and Jarda T. Wroblewski
Molecular Pharmacology August 1, 2012, 82 (2) 291-301; DOI: https://doi.org/10.1124/mol.112.078444
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