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J. Biol. Chem., Vol. 278, Issue 10, 8146-8153, March 7, 2003
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From the Ottawa Health Research Institute, Ottawa Hospital (Civic
Campus), and Departments of Medicine/Cellular and
Molecular Medicine, University of Ottawa, Ottawa, Ontario K1Y 4K9,
Canada
A chimeric D1A dopaminergic receptor harboring
the cytoplasmic tail (CT) of the D1B subtype (D1A-CTB) has been used
previously to show that CT imparts high dopamine (DA) affinity
and constitutive activity to the D1B receptors. However, the D1A-CTB
chimera, unlike the D1B subtype, exhibits a significantly lower DA
potency for stimulating adenylyl cyclase and a drastically lower
maximal binding capacity (Bmax). Here, using a functional
complementation of chimeric D1-like receptors, we have
identified the human D1B receptor regions regulating the
intramolecular relationships that lead to an increased DA potency and
contribute to Bmax. We demonstrate that the addition of
variant residues of the third extracellular loop (EL3) of the human D1B
receptor into D1A-CTB chimera leads to a constitutively active mutant
receptor displaying an increased DA affinity, potency, and
Bmax. These results strongly suggest that constitutively
active D1-like receptors can adopt multiple active conformations,
notably one that confers increased DA affinity with decreased DA
potency and Bmax and another that imparts increased DA
affinity with a strikingly increased DA potency and Bmax.
Overall, we show that a novel molecular interplay between EL3
and CT regulates multiple active conformations of D1-like receptors and
may have potential implications for other G protein-coupled receptor classes.
Insight into the Mechanism of Dopamine D1-like Receptor
Activation
EVIDENCE FOR A MOLECULAR INTERPLAY BETWEEN THE THIRD
EXTRACELLULAR LOOP AND THE CYTOPLASMIC TAIL*
,
*
This work was supported by Operating Grant 203694 from the
Natural Sciences and Engineering Research Council of Canada (to M. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Holder of an Ontario Graduate Scholarship in Science and
Technology from the Government of Ontario and Ottawa Health Research Institute.
§
Recipient of the K. M. Hunter doctoral research award from the
Canadian Institutes of Health Research.
¶
To whom correspondence should be addressed: Ottawa Health
Research Institute, Moses and Rose Loeb Research Centre, 725 Parkdale Ave., Ottawa, Ontario K1Y 4K9, Canada. Tel.: 613-798-5555 (ext. 18749); Fax: 613-761-5365; E-mail: mtiberi@ohri.ca.
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