Mechanism of action of clozapine in the context of dopamine D(1)-D(2) receptor hetero-dimerization - a working hypothesis.
Journal Title: Pharmacological Reports - Year 2008, Vol 60, Issue 5
Abstract
The tight correlation between the clinical potency and the D(2)R blocking action of antipsychotic medications suggests that dopamine hyperactivity plays a significant role in psychosis. Clozapine, one of the most effective antipsychotic drugs, has been shown to display moderate affinity for various neurotransmitter receptors, including the dopamine D(1) and D(2) receptors; however, the exact mechanism of action of clozapine has not yet been fully elucidated. Here, we describe our working hypothesis pointing to the role of dopamine D(1)-D(2) receptor hetero-dimerization as a mechanism of action of clozapine. It has been widely assumed that D(1) and D(2) receptors are segregated to separate neuronal populations; however, other data suggest that D(1) and D(2) receptors are co-expressed by a moderate to substantial proportion of striatal neurons, as well as in the medial prefrontal cortex. Our recent studies indicate that concomitant stimulation of both D(1) and D(2) dopamine receptors induces an increase in their hetero-dimerization. In order to confirm the working hypothesis that clozapine influences D(1)-D(2) receptor oligomerization, we employed fluorescence resonance energy transfer (FRET) technology, using fluorescently tagged dopamine receptors and fluorescence lifetime microscopy of intact living cells. The effect of clozapine on D(1)R-D(2)R hetero-oligomerization was strongly dependent on the drug concentration; the lower concentration, which resulted in binding to the high affinity sites, decreased the transfer efficiency, while the higher concentration of clozapine enhanced transfer efficiency. Further investigation confirmed the idea that high affinity binding sites exist when the receptor is coupled with G protein, and also that clozapine attenuates the hetero-oligomerization of a high affinity pool of dopamine D(1)-D(2) receptors. The results discussed in the present study, showing the effect of clozapine on D(1)-D(2) receptor hetero-oligomerization, together with the data pointing to the importance of receptors forming hetero-oligomers as a novel level for pharmacological intervention help to increase the understanding of the molecular mechanism of action of antipsychotic drugs.
Authors and Affiliations
Marta Dziedzicka-Wasylewska, Agata Faron-Górecka, Andrzej Górecki, Maciej Kuśmider
Keywords
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