Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior

Noelle 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, Fernanda Laezza, Cheryl S. Watson, James M. Briggs, Kathryn Cunningham

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1615-1630
Number of pages16
JournalJournal of Neuroscience
Volume33
Issue number4
DOIs
StatePublished - Jan 23 2013

Fingerprint

Receptor, Serotonin, 5-HT2C
Phosphoric Monoester Hydrolases
Peptides
Serotonin
Tensins
Peptide Fragments
Phosphoprotein Phosphatases
Catalytic Domain
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior. / Anastasio, Noelle; Gilbertson, Scott R.; Bubar, Marcy J.; Agarkov, Anton; Stutz, Sonja J.; Jeng, Yowjiun; Bremer, Nicole M.; Smith, Thressa D.; Fox, Robert G.; Swinford, Sarah E.; Seitz, Patricia K.; Charendoff, Marc N.; Craft, John W.; Laezza, Fernanda; Watson, Cheryl S.; Briggs, James M.; Cunningham, Kathryn.

In: Journal of Neuroscience, Vol. 33, No. 4, 23.01.2013, p. 1615-1630.

Research output: Contribution to journalArticle

Anastasio, N, Gilbertson, SR, Bubar, MJ, Agarkov, A, Stutz, SJ, Jeng, Y, Bremer, NM, Smith, TD, Fox, RG, Swinford, SE, Seitz, PK, Charendoff, MN, Craft, JW, Laezza, F, Watson, CS, Briggs, JM & Cunningham, K 2013, 'Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior', Journal of Neuroscience, vol. 33, no. 4, pp. 1615-1630. https://doi.org/10.1523/JNEUROSCI.2656-12.2013
Anastasio, Noelle ; Gilbertson, Scott R. ; Bubar, Marcy J. ; Agarkov, Anton ; Stutz, Sonja J. ; Jeng, Yowjiun ; Bremer, Nicole M. ; Smith, Thressa D. ; Fox, Robert G. ; Swinford, Sarah E. ; Seitz, Patricia K. ; Charendoff, Marc N. ; Craft, John W. ; Laezza, Fernanda ; Watson, Cheryl S. ; Briggs, James M. ; Cunningham, Kathryn. / Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 4. pp. 1615-1630.
@article{f8c655cac39b403bae185bcc02c8df24,
title = "Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior",
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.",
author = "Noelle Anastasio and Gilbertson, {Scott R.} and Bubar, {Marcy J.} and Anton Agarkov and Stutz, {Sonja J.} and Yowjiun Jeng and Bremer, {Nicole M.} and Smith, {Thressa D.} and Fox, {Robert G.} and Swinford, {Sarah E.} and Seitz, {Patricia K.} and Charendoff, {Marc N.} and Craft, {John W.} and Fernanda Laezza and Watson, {Cheryl S.} and Briggs, {James M.} and Kathryn Cunningham",
year = "2013",
month = "1",
day = "23",
doi = "10.1523/JNEUROSCI.2656-12.2013",
language = "English (US)",
volume = "33",
pages = "1615--1630",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "4",

}

TY - JOUR

T1 - Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior

AU - Anastasio, Noelle

AU - Gilbertson, Scott R.

AU - Bubar, Marcy J.

AU - Agarkov, Anton

AU - Stutz, Sonja J.

AU - Jeng, Yowjiun

AU - Bremer, Nicole M.

AU - Smith, Thressa D.

AU - Fox, Robert G.

AU - Swinford, Sarah E.

AU - Seitz, Patricia K.

AU - Charendoff, Marc N.

AU - Craft, John W.

AU - Laezza, Fernanda

AU - Watson, Cheryl S.

AU - Briggs, James M.

AU - Cunningham, Kathryn

PY - 2013/1/23

Y1 - 2013/1/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84872696152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872696152&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2656-12.2013

DO - 10.1523/JNEUROSCI.2656-12.2013

M3 - Article

VL - 33

SP - 1615

EP - 1630

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 4

ER -