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T he ability to form spatial complexes allowing molecular interactions between receptor protomers facilitates cooperative effects and tissue specific control of neuronal activity. Thus, heterodimerization is discussed as an integral feature of G-protein coupled receptor (GPCR) mediated signal transduction. 1À3 Intramembrane receptorÀreceptor interactions of associated protomers may modify binding and activating properties of GPCR ligands. 4À7 Using F€ orster resonance energy transfer (FRET) technique, a recent study on the interactions between R 2A -adrenergic and μ-opioid receptors demonstrated a transinhibitory effect between the protomers. In detail, morphine binding to the μ-opioid receptor triggered the conformational changes in the norepinephrine-occupied R 2A -adrenergic receptor leading to the inhibition of its signaling. 8 Physical interactions between δ-and μ-opioid receptors were suggested to modulate μ-mediated tolerance and dependence 9 when the development of bivalent ligands was constituted as a useful approach to investigate changes in receptor properties as a consequence to dimerization. 10,11 Heterodimerization is also a highly relevant phenomenon for dopamine receptor mediated signaling. 12,13 Demonstrating the development of a new complex with enhanced functional activity through hetero-oligomerization, the physical interaction between the dopamine D 2L and the somatostatin SST5 receptor was investigated via radioligand binding studies, functional assays, and FRET microscopy. 14 The heterooligomerization of D 2L and SST5, known for their colocalization in the central nervous system (CNS), led to a synergistic effect on binding and signaling as molecular cross-talk and the correlation between activated receptor function and oligomerization was stressed.Dopaminergic systems have been also described to functionally interact with the neuromodulatory peptide neurotensin (NT, pE-L-Y-E-N-K-P-R-R-P-Y-I-L) 15 which is suggested to play a role in the pathophysiology of brain diseases including schizophrenia, Parkinson's disease. and Morbus Alzheimer. 16À18 Thus, neurotensin was shown to negatively alter binding affinity of the dopamine receptor agonist [ 3 H]N-n-propyl-nor-apomorphine in specific brain areas. 19À25 However, biomolecular interactions and a putative heteromer formation between dopamine receptors and neurotensin receptors have not been investigated yet.Employing fluorescence detected coimmunoprecipitation and radioligand binding experiments, we herein demonstrate that coexpression of dopamine D 2L receptor and the neurotensin receptor subtype NTS 1 in human embryonic kidney cells (HEK293 cells) leads to physical interaction at a molecular level. In this in vitro system, a trans-inhibitory effect on the agonist binding affinity of D 2 was observed in the presence of neurotensin. A biochemical fingerprint 26 of the D 2L -NTS 1 heteromer was explored by investigating the effect of both neurotensin and NTS 1 on the D 2 receptor binding properties of different ABSTRACT: Dopaminergic systems ...

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