Allosteric Modulation of Dopamine D 2 Receptors by Homocysteine

Department of Biochemistry and Molecular Biology (Facultad de Biología), University of Barcelona, Barcino, Catalonia, Spain
Journal of Proteome Research (Impact Factor: 4.25). 12/2006; 5(11):3077-83. DOI: 10.1021/pr0601382
Source: PubMed


It has been suggested that L-DOPA-induced hyperhomocysteinemia can increase the risk of stroke, heart disease, and dementia and is an additional pathogenetic factor involved in the progression of Parkinson's disease. In Chinese hamster ovary (CHO) cells stably cotransfected with adenosine A(2A) and dopamine D2 receptors, homocysteine selectively decreased the ability of D2 receptor stimulation to internalize adenosine A(2A)-dopamine D2 receptor complexes. Radioligand-binding experiments in the same cell line demonstrated that homocysteine acts as an allosteric D2 receptor antagonist, by selectively reducing the affinity of D2 receptors for agonists but not for antagonists. Mass spectrometric analysis showed that, by means of an arginine (Arg)-thiol electrostatic interaction, homocysteine forms noncovalent complexes with the two Arg-rich epitopes of the third intracellular loop of the D2 receptor, one of them involved in A(2A)-D2 receptor heteromerization. However, homocysteine was unable to prevent or disrupt A(2A)-D2 receptor heteromerization, as demonstrated with Fluorescence Resonance Energy Transfer (FRET) experiments in stably cotransfected HEK cells. The present results could have implications for Parkinson's disease.

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    • "Another possible mechanism of the role of Hcy in dopaminergic transmission has been presented by Agnati et al. [55], and allosteric modulation of dopamine D2 receptors showed that Hcy acted as an allosteric D2 receptor antagonist in an animal model, selectively reducing the affinity of D2 receptors for agonists but not for antagonists. The molecular mechanism of this modulation showed that Hcy forms non-covalent complexes with two arginine (Arg)-rich epitopes of the third intracellular loop of the D2 receptor [55]. These implications may result in the complications seen in PD therapy, such as the effect of high levels of Hcy on the reactivity of patients to L-dopa and dopamine agonists commonly used in the treatment of PD. "
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