Constitutive activity of a chimeric D2/D1 dopamine receptor

Laura B. Kozell, Kim A. Neve

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56 Scopus citations


Chimeric D1/D2 receptors were constructed to identify structural determinants of drug affinity and efficacy. We previously reported that chimeras that had D1 receptor transmembrane domain VII together with amino- terminal sequence from the D2 receptor were nonfunctional. D2/D1 chimeras were constructed that contained D2 receptor sequence at the amino- and carboxyl-terminal ends and D1 receptor sequence in the intervening region. Chimeric receptors with D2 sequence from transmembrane domain 7 to the carboxyl terminus together with D2 receptor sequence from the amino terminus through transmembrane helix 4 (D(2[1-4,7])) and 5 (D(2[1-5,7])) bound [3H]spiperone with high affinity, consistent with the hypothesis that Ds receptor transmembrane domain I or II is incompatible with D1 receptor transmembrane domain VII. D(2[1-4,7]) and D(2[1-5,7]) had affinities similar to D1 and D2 receptors for most nonselective dopamine antagonists and had affinities for most of the selective antagonists that were intermediate between those of the parent receptors. D(2[1-4,7]) and D(2[1-5,7]) mediated dopamine receptor agonist-induced stimulation and inhibition, respectively, of cAMP accumulation. The more efficient coupling of D(2[1-5,7] to inhibition of cAMP accumulation, compared with the coupling of D(2[5-7) and D(2[3-7]), supports the view that multiple D2 receptor cytoplasmic domains acting in concert are necessary for receptor activation of G(i). In contrast, D(2[1- 4,7]), which contains only one cytoplasmic loop (the third) from the D1 receptor, is capable of activating G(s). D(2[1-4,7]) exhibited several characteristics of a constitutively active receptor, including enhanced basal (unliganded) stimulation of cAMP accumulation, high affinity for agonists even n the presence of GTP, and blunted agonist-stimulated cAMP accumulation. A number of dopamine receptor antagonists were inverse agonists at D(2[14,7], inhibiting basal cAMP accumulation. Some of these drugs were also inverse agonists at the D1 receptor. Interestingly, several antagonists also potentiated forskolin-stimulated cAMP accumulation via D(2[1-5,7] and via the D2 receptor, which could reflect inverse agonist inhibition of native constitutive activity of this receptor.

Original languageEnglish (US)
Pages (from-to)1137-1149
Number of pages13
JournalMolecular pharmacology
Issue number6
StatePublished - Dec 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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