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Articles, Cellular/Molecular

Peptide Inhibitors Disrupt the Serotonin 5-HT2C Receptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior

Noelle C. Anastasio, Scott R. Gilbertson, Marcy J. Bubar, Anton Agarkov, Sonja J. Stutz, Yowjiun Jeng, Nicole M. Bremer, Thressa D. Smith, Robert G. Fox, Sarah E. Swinford, Patricia K. Seitz, Marc N. Charendoff, John W. Craft Jr, Fernanda M. Laezza, Cheryl S. Watson, James M. Briggs and Kathryn A. Cunningham
Journal of Neuroscience 23 January 2013, 33 (4) 1615-1630; DOI: https://doi.org/10.1523/JNEUROSCI.2656-12.2013
Noelle C. Anastasio
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Scott R. Gilbertson
1Center for Addiction Research and
4Departments of Chemistry and
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Marcy J. Bubar
1Center for Addiction Research and
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Anton Agarkov
4Departments of Chemistry and
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Sonja J. Stutz
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Yowjiun Jeng
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
3Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, and
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Nicole M. Bremer
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Thressa D. Smith
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Robert G. Fox
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Sarah E. Swinford
1Center for Addiction Research and
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Patricia K. Seitz
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Marc N. Charendoff
5Biology and Biochemistry, University of Houston, Houston, Texas 77004
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John W. Craft Jr
5Biology and Biochemistry, University of Houston, Houston, Texas 77004
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Fernanda M. Laezza
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Cheryl S. Watson
1Center for Addiction Research and
3Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, and
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James M. Briggs
5Biology and Biochemistry, University of Houston, Houston, Texas 77004
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Kathryn A. Cunningham
1Center for Addiction Research and
2Departments of Pharmacology and Toxicology and
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Abstract

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT2C receptor (5-HT2CR) is essential in normal physiology, whereas aberrant 5-HT2CR function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT2CR interacts with specific protein partners, but the impact of such interactions on 5-HT2CR function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT2CR and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT2CR-mediated biology but not that of the closely homologous 5-HT2AR. A peptide derived from the third intracellular loop of the human 5-HT2CR [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT2CR-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT2CR signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT2CR allostery and therapeutics for 5-HT2CR-mediated disorders.

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The Journal of Neuroscience: 33 (4)
Journal of Neuroscience
Vol. 33, Issue 4
23 Jan 2013
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Peptide Inhibitors Disrupt the Serotonin 5-HT2C Receptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior
Noelle C. Anastasio, Scott R. Gilbertson, Marcy J. Bubar, Anton Agarkov, Sonja J. Stutz, Yowjiun Jeng, Nicole M. Bremer, Thressa D. Smith, Robert G. Fox, Sarah E. Swinford, Patricia K. Seitz, Marc N. Charendoff, John W. Craft Jr, Fernanda M. Laezza, Cheryl S. Watson, James M. Briggs, Kathryn A. Cunningham
Journal of Neuroscience 23 January 2013, 33 (4) 1615-1630; DOI: 10.1523/JNEUROSCI.2656-12.2013

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Peptide Inhibitors Disrupt the Serotonin 5-HT2C Receptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior
Noelle C. Anastasio, Scott R. Gilbertson, Marcy J. Bubar, Anton Agarkov, Sonja J. Stutz, Yowjiun Jeng, Nicole M. Bremer, Thressa D. Smith, Robert G. Fox, Sarah E. Swinford, Patricia K. Seitz, Marc N. Charendoff, John W. Craft Jr, Fernanda M. Laezza, Cheryl S. Watson, James M. Briggs, Kathryn A. Cunningham
Journal of Neuroscience 23 January 2013, 33 (4) 1615-1630; DOI: 10.1523/JNEUROSCI.2656-12.2013
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