QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.024612v1 70/4/1264    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, C. Articles by Teitler, M. Search for Related Content PubMed PubMed Citation Articles by Smith, C. Articles by Teitler, M.

Risperidone Irreversibly Binds to and Inactivates the h5-HT₇ Serotonin Receptor

Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, New York

Risperidone displays a novel mechanism of antagonism of the h5-HT₇ receptor. Pretreatment of the cells with 5 or 20 nM risperidone, followed by removal of the drug from the media, renders the 5-HT₇ receptors unresponsive to 10 µM 5-HT for at least 24 h. Thus, risperidone seems 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 green fluorescent protein-labeled fluorescent forms of the h5-HT₇ receptor exposed to 20 nM 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 that the h5-HT₇ receptor may possess unique structural features that allow 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 subfamily of G-protein-coupled receptors (GPCRs) possessing this property or that many GPCRs 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.

Address correspondence to: Dr. Milt Teitler, A-136, Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208. E-mail: teitlem{at}mail.amc.edu

This article has been cited by other articles:

				M. R. Bruchas, T. Yang, S. Schreiber, M. DeFino, S. C. Kwan, S. Li, and C. Chavkin Long-Acting {kappa} Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase J. Biol. Chem., October 12, 2007; 282(41): 29803 - 29811. [Abstract] [Full Text] [PDF]