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Research ArticleCELLULAR AND MOLECULAR

Blockade of G Protein-Coupled Receptors and the Dopamine Transporter by a Transmembrane Domain Peptide: Novel Strategy for Functional Inhibition of Membrane Proteins in Vivo

Susan R. George, Gordon Y. K. Ng, Samuel P. Lee, Theresa Fan, George Varghese, Chen Wang, Charles M. Deber, Philip Seeman and Brian F. O'Dowd
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 481-489; DOI: https://doi.org/10.1124/jpet.103.053843
Susan R. George
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Gordon Y. K. Ng
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Samuel P. Lee
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Theresa Fan
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George Varghese
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Chen Wang
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Charles M. Deber
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Philip Seeman
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Brian F. O'Dowd
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Abstract

G protein-coupled receptors have a core consisting of seven transmembrane α-helices that is important in maintaining the structure of the receptor. We postulated that disruption of the transmembrane core may interfere with receptor function. In this study, the function of integral membrane proteins was disrupted in vivo using peptides mimicking their transmembrane domains. A peptide derived from transmembrane 7 of the D2 dopamine receptor injected unilaterally into caudate nucleus of rats challenged with apomorphine resulted in rotational behavior, indicating D2 receptor blockade. No rotational behavior was seen with a similar peptide based on the β2 adrenergic receptor and the D2 transmembrane peptide did not affect the D1 dopamine receptor, indicating that the D2 receptor-derived peptide had a specific effect. The intravenous administration of a transmembrane peptide derived from the α1-adrenergic receptor resulted in lowered arterial blood pressure and injection of a β1-adrenergic receptor peptide resulted in decreased heart rate. Injection of a V2 vasopressin receptor-derived transmembrane peptide resulted in increased urine output, suggesting antagonism of the effects of vasopressin. Finally, dopamine release in rat brain after cocaine administration was blocked by a transmembrane peptide based on the dopamine transporter. Circular dichroism spectroscopy of the peptides revealed α-helical structure similar to that of native transmembrane domains. Thus, transmembrane peptides can disrupt membrane proteins in vivo likely by competing with native transmembrane domains. The disruption of the hydrophobic core architecture of membrane proteins represents a novel mechanism of achieving functional inhibition that may be possible to exploit in developing novel therapeutics.

Footnotes

  • ↵1 Current address: Amgen, One Amgen Center Dr., Thousand Oaks, CA 91320-1799.

  • DOI: 10.1124/jpet.103.053843.

  • This work was supported by grants from the Canadian Institutes of Health Research, the National Institute on Drug Abuse, and the Natural Sciences and Engineering Research Council of Canada, and by a Canada Research Chair to S.R.G.

  • ABBREVIATIONS: GPCR, G protein-coupled receptor; TM, transmembrane; DAT, dopamine transporter; PE, polyethylene; CD, circular dichroism; SCH 23390, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine.

    • Received May 2, 2003.
    • Accepted July 31, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleCELLULAR AND MOLECULAR

Blockade of G Protein-Coupled Receptors and the Dopamine Transporter by a Transmembrane Domain Peptide: Novel Strategy for Functional Inhibition of Membrane Proteins in Vivo

Susan R. George, Gordon Y. K. Ng, Samuel P. Lee, Theresa Fan, George Varghese, Chen Wang, Charles M. Deber, Philip Seeman and Brian F. O'Dowd
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 481-489; DOI: https://doi.org/10.1124/jpet.103.053843

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Research ArticleCELLULAR AND MOLECULAR

Blockade of G Protein-Coupled Receptors and the Dopamine Transporter by a Transmembrane Domain Peptide: Novel Strategy for Functional Inhibition of Membrane Proteins in Vivo

Susan R. George, Gordon Y. K. Ng, Samuel P. Lee, Theresa Fan, George Varghese, Chen Wang, Charles M. Deber, Philip Seeman and Brian F. O'Dowd
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 481-489; DOI: https://doi.org/10.1124/jpet.103.053843
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