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Molecular Pharmacology

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Research ArticleArticle

Risperidone-Induced Inactivation and Clozapine-Induced Reactivation of Rat Cortical Astrocyte 5-Hydroxytryptamine7 Receptors: Evidence for In Situ G Protein-Coupled Receptor Homodimer Protomer Cross-Talk

Carol Smith, Nicole Toohey, Jessica A. Knight, Michael T. Klein and Milt Teitler
Molecular Pharmacology February 2011, 79 (2) 318-325; DOI: https://doi.org/10.1124/mol.110.069278
Carol Smith
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Nicole Toohey
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Jessica A. Knight
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Michael T. Klein
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Milt Teitler
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Abstract

We have reported previously novel drug-induced inactivation and reactivation of human 5-hydroxytryptamine7 (5-HT7) receptors in a recombinant cell line. To explain these novel observations, a homodimer structure displaying protomer-protomer cross-talk was proposed. To determine whether these novel observations and interpretations are due to an artifactual G protein-coupled receptor (GPCR) mechanism unique to the recombinant cell line, we explored the properties of r5-HT7 receptors expressed by cortical astrocytes in primary culture. As in the recombinant cell line, risperidone, 9-OH-risperidone, methiothepin, and bromocriptine were found to potently inactivate r5-HT7 receptors. As in the recombinant cell line, exposure of risperidone-inactivated astrocyte r5-HT7 receptors to competitive antagonists resulted in the reactivation of r5-HT7 receptors. The potencies of the reactivating drugs closely correlated with their affinities for h5-HT7 receptors. These results indicate the novel inactivating and reactivating property of drugs is not due to an artifact of the recombinant cell line expressing h5-HT7 receptors but is an intrinsic property of 5-HT7 receptors in vitro and ex vivo. This evidence suggests that a native (nonmutated) GPCR, in its native membrane environment (cortical astrocyte primary culture), can function as a homodimer with protomer-protomer cross-talk. Homodimers may be a common GPCR structure. The experimental design used in our studies can be used to explore the properties of other GPCRs in their native forms in recombinant cells, primary cultures expressing the endogenous GPCRs, and possibly in vivo. The homodimer structure and protomer-protomer cross-talk offer new avenues of research into receptor dysfunction in disease states and the development of novel drugs.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Mental Health [Grant MH56650].

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

    doi:10.1124/mol.110.069278.

  • ABBREVIATIONS:

    5-HT
    5-hydroxytryptamine
    GPCR
    G protein-coupled receptor
    HEK
    human embryonic kidney
    HBSS
    Hanks' balanced salt solution
    TR-FRET
    time-resolved fluorescence energy transfer
    MEM
    minimum essential medium
    PBS
    phosphate-buffered saline
    SB269970
    (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride
    SB270146
    5-chloro-N-[4-methoxy-3-(1-piperazinyl)phenyl]-3-methyl-benzo[b]thiophen-2-sulfonamide hydrochloride
    ICI169369
    2-(2-dimethylamino ethylthio)-3-phenyl quinoline.

  • Received October 8, 2010.
  • Accepted November 9, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
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Research ArticleArticle

Risperidone-Induced Inactivation and Clozapine-Induced Reactivation of Rat Cortical Astrocyte 5-Hydroxytryptamine7 Receptors: Evidence for In Situ G Protein-Coupled Receptor Homodimer Protomer Cross-Talk

Carol Smith, Nicole Toohey, Jessica A. Knight, Michael T. Klein and Milt Teitler
Molecular Pharmacology February 1, 2011, 79 (2) 318-325; DOI: https://doi.org/10.1124/mol.110.069278

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Research ArticleArticle

Risperidone-Induced Inactivation and Clozapine-Induced Reactivation of Rat Cortical Astrocyte 5-Hydroxytryptamine7 Receptors: Evidence for In Situ G Protein-Coupled Receptor Homodimer Protomer Cross-Talk

Carol Smith, Nicole Toohey, Jessica A. Knight, Michael T. Klein and Milt Teitler
Molecular Pharmacology February 1, 2011, 79 (2) 318-325; DOI: https://doi.org/10.1124/mol.110.069278
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