Allosteric modulation of dopamine D2 receptors by homocysteine

Luigi F. Agnati, Sergi Ferré, Susanna Genedani, Giuseppina Leo, Diego Guidolin, Monica Filaferro, Paulina Carriba, Vicent Casadó, Carme Lluis, Rafael Franco, Amina S. Woods, Kjell Fuxe

Research output: Contribution to journalArticle

Abstract

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 A2A-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.

Original languageEnglish (US)
Pages (from-to)3077-3083
Number of pages7
JournalJournal of Proteome Research
Volume5
Issue number11
DOIs
StatePublished - Nov 2006
Externally publishedYes

Keywords

  • Allosteric modulation
  • Dopamine D receptor
  • Homocysteine
  • Mass spectrometry
  • Parkinson's disease

ASJC Scopus subject areas

  • Genetics
  • Biotechnology
  • Biochemistry

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  • Cite this

    Agnati, L. F., Ferré, S., Genedani, S., Leo, G., Guidolin, D., Filaferro, M., Carriba, P., Casadó, V., Lluis, C., Franco, R., Woods, A. S., & Fuxe, K. (2006). Allosteric modulation of dopamine D2 receptors by homocysteine. Journal of Proteome Research, 5(11), 3077-3083. https://doi.org/10.1021/pr0601382