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First published on July 26, 2006; DOI: 10.1124/mol.106.024612

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Received for publication March 21, 2006.
Revised July 26, 2006.
Accepted for publication July 26, 2006.

Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor

Carol Smith 1, Tariq Rahman 1, Nicole Toohey 1, Joseph Mazurkiewicz 2, Katharine Herrick-Davis 1, Milt Teitler 1*

1 Albany Medical College 2 Albany Medical COllege

* Address correspondence to: E-mail: teitlem{at}mail.amc.edu

Abstract

Risperidone displays a novel mechanism of antagonism of the h5-HT7 receptor. Pre-treatment of the cells with 5nM or 20nM risperidone, followed by removal of the drug from the media, renders the 5-HT7 receptors unresponsive to 10µM 5-HT for at least 24 hrs. Thus risperidone appears to be producing a rapid, long-lasting inactivation of the h5-HT7 receptor. Whole cell radioligand binding studies indicate that risperidone interacts in an irreversible or pseudo-irreversible manner with the h5-HT7 receptor thus producing the inactivation. Internalization of the h5-HT7 receptor was not detected by monitoring GFP-labeled fluorescent forms of the h5-HT7 receptor exposed to 20nM risperidone. Ten other antagonists were tested for h5-HT7-inactivating properties and only 9-OH-risperidone and methiothepin were found to demonstrate the same anomalous properties as risperidone. These results indicate the h5-HT7 receptor may possess unique structural features allowing certain drugs to induce a conformation resulting in an irreversible interaction in the intact membrane environment. This may indicate that the h5-HT7 receptor is part of a sub-family of GPCR possessing this property or that many GPCR have the potential to be irreversibly blocked, but only select drugs can induce this effect. At the very least the possibility that highly prescribed drugs, such as risperidone, are irreversibly antagonizing GPCR function in vivo is noteworthy.


Key words: Serotonin, Gs family, Gq/11 family, cAMP, IP3/DAG, Desensitization/uncoupling, Sequestration/Internalization, Anti-psychotics


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