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Critical interaction of the dopamine D 1 receptor with ergolines: the roles of conserved aromatic residues in transmembrane six segment (656.5)
Author(s) -
Lee SangMin,
Mailman Richard
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.656.5
Subject(s) - receptor , transmembrane domain , homology modeling , alanine , docking (animal) , potency , transmembrane protein , chemistry , biochemistry , stereochemistry , biology , in vitro , enzyme , amino acid , medicine , nursing
We have investigated the interaction of the dopamine D 1 receptor with ergoline‐based ligands to understand how non‐catechols activate this receptor. Here, we examined the roles of conserved aromatic residues (F6.51 and F6.52) in transmembrane six segment that are reported to be conserved sites for receptor activation. Mutations of F6.51 and F6.52 to alanine (F6.51A and F6.52A) dramatically decreased the binding affinity of ergolines. Consistent with the affinity data, the functional potency of these ligands at D 1 ‐mediated cAMP synthesis was eliminated at the F6.51A receptor. Whereas F6.52A significantly reduced the potency of these ergolines (consistent with their decreased affinity), it did not decrease the maximal cAMP production. We also studied F6.51Y and F6.51W that were more likely to conserve aromatic/hydrophobic interactions of F6.51. Although F6.51Y did not restore the affinity decrease by F6.51A, it partially restored the potency and fully restored cAMP production. F6.51W was essentially identical to the wild‐type receptor in terms of both affinity and activity of the ergolines. Using a D 1 receptor homology model, we hypothesize that the B and D ring of the ergoline backbone has a docking pose close to F6.52 and F6.51, respectively. The F6.51W mutation mimics the hydrophobic interaction that ergolines have with the wild‐type receptor. These data can be useful for designing non‐catechol agonists for the D 1 receptor.Grant Funding Source : Supported by Grant PDF‐SFW‐1208 from the Parkinson's Disease Foundation