Abstract
Numerous mutant G protein-coupled receptors with diminished or no function have been described that are naturally occurring or that are the product of gene manipulation. It has largely been assumed that receptor mutants do not affect the function of the wild-type receptor; however, the occurrence of G protein-coupled receptor dimerization suggests the possibility that an intermolecular interaction between mutant and wild-type receptors can occur. We have shown previously that the D2 dopamine receptor (D2DR) exists as dimers in cell lines and brain tissue. In this study, we demonstrated that mutant D2DR can modulate the function of the wild-type D2DR. While attempting to elucidate the structure of the D2DR dimer, we demonstrated that nonfunctional D2DR substitution and truncation mutants antagonized wild-type D2DR function. Furthermore, from analyses of this interaction between the receptor mutants and the D2DR, using photoaffinity labeling, we provide evidence that the D2DR is oligomeric in the cell.
Footnotes
- Received November 5, 1999.
- Accepted March 28, 2000.
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Dr. Susan R. George, Department of Pharmacology, University of Toronto, Room 4358, Medical Sciences Blgd., 1 King's College Circle, Toronto, ON M5S 1A8, Canada. E-mail:s.george{at}utoronto.ca.
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↵1 Current address: Merck Frosst Center for Therapeutic Research, Kirkland, QC H9H 3L1, Canada.
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↵2 Current address: Pharmaco Genesis, 6628 Heather Heath Lane, West Bloomfield, MI, 48322.
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This work was supported by grants from the Medical Research Council of Canada, the National Institute on Drug Abuse, the Smokeless Tobacco Research Council, an Addiction Research Foundation Fellowship to S.P.L., and a Medical Research Council of Canada Fellowship to G.N.
- The American Society for Pharmacology and Experimental Therapeutics
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