D2/D3 Dopamine Receptor Heterodimers Exhibit Unique Functional Properties

Marco Scarselli, Francesca Novi, Ester Schallmach, Ridwan Lin, Alessandra Baragli, Anna Colzi, Nathalie Griffon, Giovanni U. Corsini, Pierre Sokoloff, Robert Levenson, Zvi Vogel, Roberto Maggio

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Abstract

Evidence for heterodimerization has recently been provided for dopamine D1 and adenosine A1 receptors as well as for dopamine D2 and somatostatin SSTR5 receptors. In this paper, we have studied the possibility that D2 and D3 receptors interact functionally by forming receptor heterodimers. Initially, we split the two receptors at the level of the third cytoplasmic loop into two fragments. The first, containing transmembrane domains (TM) I to V and the N-terminal part of the third cytoplasmic loop, was named D2trunk or D 3trunk, and the second, containing the C-terminal part of the third cytoplasmic loop, TMVI and TMVII, and the C-terminal tail, was named D 2tail or D3tail. Then we defined the pharmacological profiles of the homologous (D2trunk/ D2tail and D 3trunk/D3tail) as well as of the heterologous (D 2trunk/D3tail and D3trunk/D2tail) cotransfected receptor fragments. The pharmacological profile of the cross-cotransfected fragments was different from that of the native D 2 or D3 receptors. In most cases, the D 3trunk/D2tail was the one with the highest affinity for most agonists and antagonists. Moreover, we observed that all of these receptor fragments reduced the expression of the wild type dopamine D2 and D3 receptors, suggesting that D2 and D3 receptors can form complexes with these fragments and that these complexes bind [3H]nemonapride less efficiently or are not correctly targeted to the membrane. In a second set of experiments, we tested the ability of the split and the wild type receptors to inhibit adenylyl cyclase (AC) types V and VI. All of the native and split receptors inhibited AC-V and AC-VI, with the exception of D3, which was unable to inhibit AC-VI. We therefore studied the ability of D2 and D3 to interact functionally with one another to inhibit AC-VI. We found that with D2 alone, R-(+)-7-hydroxydypropylaminotetralin hydrobromide inhibited AC-VI with an IC50 of 2.05 ± 0.15 nM, while in the presence of D 2 and D3 it inhibited AC-VI with an IC50 of 0.083 ± 0.011 nM. Similar results were obtained with a chimeric cyclase made from AC-V and AC-VI. Coimmunoprecipitation experiments indicate that D 2 and D3 receptors are capable of physical interaction.

Original languageEnglish (US)
Pages (from-to)30308-30314
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number32
DOIs
StatePublished - Aug 10 2001

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Scarselli, M., Novi, F., Schallmach, E., Lin, R., Baragli, A., Colzi, A., Griffon, N., Corsini, G. U., Sokoloff, P., Levenson, R., Vogel, Z., & Maggio, R. (2001). D2/D3 Dopamine Receptor Heterodimers Exhibit Unique Functional Properties. Journal of Biological Chemistry, 276(32), 30308-30314. https://doi.org/10.1074/jbc.M102297200