Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved November 16, 2007
January 22, 2008
105 (3) 1079-1084
Commentary
Arresting serotonin
Atheir Abbas, Bryan L. Roth

Abstract

Visual and auditory hallucinations accompany certain neuropsychiatric disorders, such as schizophrenia, and they also can be induced by the use or abuse of certain drugs. The heptahelical serotonin 2A receptors (5-HT2ARs) are molecular targets for drug-induced hallucinations. However, the cellular mechanisms by which the 5-HT2AR mediates these effects are not well understood. Drugs acting at the 5-HT2AR can trigger diverse signaling pathways that may be directed by the chemical properties of the drug. β-arrestins are intracellular proteins that bind to heptahelical receptors and represent a point where such divergences in ligand-directed functional signaling could occur. Here we compare the endogenous agonist, serotonin, to a synthetic 5-HT2AR hallucinogenic agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), in mice lacking β-arrestin-2, as well as in cells lacking β-arrestins. In mice, we find that serotonin induces a head twitch response by a β-arrestin-2-dependent mechanism. However, DOI invokes the behavior independent of β-arrestin-2. The two structurally distinct agonists elicit different signal transduction and trafficking patterns upon activation of 5-HT2AR, which hinge on the presence of β-arrestins. Our study suggests that the 5-HT2AR–β-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.

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ACKNOWLEDGMENTS.

We thank Dr. Robert J. Lefkowitz (Duke University, Durham, NC) for WT and β-arrestin-1- and β-arrestin-2-KO MEFs, as well as the β-arrestin-2 mice; Dr. Marc G. Caron (Duke University) for the β-arrestin-2-YFP cDNA construct; and Lori Hudson for mouse colony maintenance and technical assistance. This work was supported by The National Institute on Drug Abuse via Training Fellowship F31DA219532 (to K.M.R.) and Grants K01 DA014600 and R01 DA18860 to (L.M.B.).

Supporting Information

Adobe PDF - 08862Fig6.pdf
Adobe PDF - 08862Fig6.pdf
Adobe PDF - 08862Fig7.pdf
Adobe PDF - 08862Fig7.pdf

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 105 | No. 3
January 22, 2008
PubMed: 18195357

Classifications

Submission history

Received: September 18, 2007
Published online: January 22, 2008
Published in issue: January 22, 2008

Keywords

  1. 5-HT2A receptor
  2. G protein-coupled receptor
  3. internalization
  4. MAP kinase
  5. schizophrenia

Acknowledgments

We thank Dr. Robert J. Lefkowitz (Duke University, Durham, NC) for WT and β-arrestin-1- and β-arrestin-2-KO MEFs, as well as the β-arrestin-2 mice; Dr. Marc G. Caron (Duke University) for the β-arrestin-2-YFP cDNA construct; and Lori Hudson for mouse colony maintenance and technical assistance. This work was supported by The National Institute on Drug Abuse via Training Fellowship F31DA219532 (to K.M.R.) and Grants K01 DA014600 and R01 DA18860 to (L.M.B.).

Notes

This article is a PNAS Direct Submission.
See Commentary on page 831.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708862105/DC1.

Authors

Affiliations

Cullen L. Schmid
Departments of Pharmacology and Psychiatry, Ohio State University College of Medicine, Columbus, OH 43210
Kirsten M. Raehal
Departments of Pharmacology and Psychiatry, Ohio State University College of Medicine, Columbus, OH 43210
Laura M. Bohn [email protected]
Departments of Pharmacology and Psychiatry, Ohio State University College of Medicine, Columbus, OH 43210

Notes

*To whom correspondence should be addressed. E-mail: [email protected]
Author contributions: C.L.S., K.M.R., and L.M.B. designed research, performed research, analyzed data, and wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo
    Proceedings of the National Academy of Sciences
    • Vol. 105
    • No. 3
    • pp. 827-1098

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