Identification of dopamine D1-D3 receptor heteromers -: Indications for a role of synergistic D1-D3 receptor interactions in the striatum

The function of dopamine D-3 receptors present in the striatum has remained elusive. In the present study evidence is provided for the existence of dopamine D-1-D-3 receptor heteromers and for an intramembrane D-1-D-3 receptor cross-talk in living cells and in the striatum. The formation of D-1-D-3 receptor heteromers was demonstrated by fluorescence resonance energy transfer and bioluminescence resonance energy transfer techniques in transfected mammalian cells. In membrane preparations from these cells, a synergistic D-1-D-3 intramembrane receptor-receptor interaction was observed, by which D3 receptor stimulation enhances D-1 receptor agonist affinity, indicating that the D-1-D-3 intramembrane receptor-receptor interaction is a biochemical characteristic of the D-1-D-3 receptor heteromer. The same biochemical characteristic was also observed in membrane preparations from brain striatum, demonstrating the striatal co-localization and heteromerization of D-1 and D-3 receptors. According to the synergistic D-1-D-3 intramembrane receptor-receptor interaction, experiments in reserpinized mice showed that D-3 receptor stimulation potentiates D-1 receptor-mediated behavioral effects by a different mechanism than D-2 receptor stimulation. The present study shows that a main functional significance of the D3 receptor is to obtain a stronger dopaminergic response in the striatal neurons that co-express the two receptors.