The role of D1 –D2 receptor hetero-dimerization in the mechanism of action of clozapine

Abstract Clozapine is effective although still not perfect drug used to treat schizophrenia. The precise mechanism of its action is not known. Here we show that there are two binding sites for clozapine at the dopamine D1 and D2 receptors, and the affinity of D1 R strongly depended on whether the re...

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Bibliographic Details
Published in:European neuropsychopharmacology 2008-09, Vol.18 (9), p.682-691
Main Authors: Faron-Górecka, Agata, Górecki, Andrzej, Kuśmider, Maciej, Wasylewski, Zygmunt, Dziedzicka-Wasylewska, Marta
Format: Article
Language:English
Subjects:
Antipsychotic Agents - metabolism
Antipsychotic Agents - pharmacology
Binding Sites - drug effects
Binding, Competitive - drug effects
Cell Line, Transformed
Clozapine - pharmacology
Dimerization
Dose-Response Relationship, Drug
Fluorescence Resonance Energy Transfer
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Humans
Internal Medicine
Models, Molecular
Point Mutation - genetics
Psychiatry
Receptors, Dopamine D1 - drug effects
Receptors, Dopamine D1 - genetics
Receptors, Dopamine D1 - metabolism
Receptors, Dopamine D2 - drug effects
Receptors, Dopamine D2 - genetics
Receptors, Dopamine D2 - metabolism
Recombinant Fusion Proteins
Transfection - methods
Tritium - metabolism
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Summary:Abstract Clozapine is effective although still not perfect drug used to treat schizophrenia. The precise mechanism of its action is not known. Here we show that there are two binding sites for clozapine at the dopamine D1 and D2 receptors, and the affinity of D1 R strongly depended on whether the receptor was present alone or together with D2 R (or its genetic variant D2Ser311Cys ) in the cell membrane, pointing to the role of receptor hetero-dimerization in the observed phenomenon. The use of fluorescence resonance energy transfer (FRET) technology, observed via fluorescence lifetime microscopy of the single cell, indicated that low concentration of clozapine (10 − 9  M), sufficient to saturate the high affinity site, uncoupled the D1 R–D2 R hetero-dimers. Therefore it has been concluded that clozapine might antagonize the effect of concomitant stimulation of both dopamine receptors, which has been shown previously to enhance the formation of hetero-dimers and to stimulate the calcium signaling pathway.
ISSN:0924-977X
DOI:10.1016/j.euroneuro.2008.05.001