Structural determinants of pharmacological specificity between D 1 and D2 dopamine receptors

Hongxiang Lan, Curtiss J. DuRand, Martha M. Teeter, Kim A. Neve

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

To test the hypothesis that pharmacological differentiation between D 1 and D2 dopamine receptors results from interactions of selective ligands with nonconserved residues lining the binding pocket, we mutated amino acid residues in the D2 receptor to the corresponding aligned residues in the D1 receptor and vice versa and expressed the receptors in human embryonic kidney 293 cells. Determinations of the affinity of the 14 mutant D2 receptors and 11 mutant D1 receptors for D1- and D2-selective antagonists, and rhodopsin-based homology models of the two receptors, identified two residues whose direct interactions with certain ligands probably contribute to ligand selectivity. The D1 receptor mutant W993.28F showed dramatically increased affinity for several D2-selective antagonists, particularly spiperone (225-fold), whereas the D2 receptor mutant Y417 7.43W had greatly decreased affinity for benzamide ligands such as raclopride (200-fold) and sulpiride (125-fold). The binding of the D 1-selective ligand R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH23390) was unaffected, indicating that SCH23390 makes little contact with these ancillary pocket residues. Mutation of A/V5.39 caused modest but consistent and reciprocal changes in affinity of the receptors for D1 and D2-selective ligands, perhaps reflecting altered packing of the interface of helices 5 and 6. We also obtained some evidence that residues in the second extracellular loop contribute to ligand binding. We conclude that additional determinants of D 1/D2 receptor-selective binding are located either in that loop or in the transmembrane helices but, like residue 5.39, indirectly influence the interactions of selective ligands with conserved residues by altering the shape of the primary and ancillary binding pockets.

Original languageEnglish (US)
Pages (from-to)185-194
Number of pages10
JournalMolecular pharmacology
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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