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The role of conserved transmembrane domain residues in the activation of the dopamine D2 receptor
Author(s) -
Tambe Mitali,
Cumbay Medhane
Publication year - 2009
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.23.1_supplement.942.6
Subject(s) - 5 ht5a receptor , transmembrane domain , receptor , dopamine receptor d2 , enzyme linked receptor , signal transduction , g protein coupled receptor , biology , microbiology and biotechnology , dopamine receptor , biochemistry
The interaction between two highly conserved amino acid residues in second (TM2) and seventh (TM7) transmembrane domains (aspartate and asparagine respectively) of GPCRs plays an important role in receptor activation and coupling specificity to different signal transduction pathways. Although single mutations of each conserved residue can selectively alter receptor signaling, reciprocal mutations in TM2 and TM7 appear to partially restore function in a receptor dependent manner. For example, reciprocal mutations in alpha2a‐adrenergic and 5HT2a serotonin receptors restores receptor function, but reciprocal mutation in the CB1cannabinoid receptor does not. We have characterized the role of the two conserved residues in the activation and signaling of the D2 dopamine receptor. We report that the D80N mutation in TM2 of the D2 receptor ablates receptor‐dependent activation of Kir 3.0 channels and significantly blunts receptor‐dependent inhibition of cyclic AMP accumulation. In contrast to the corresponding mutant (D164N) in the CB1 receptor, the D80N mutation also ablated receptor‐dependent phosphorylation of ERK1/2. We also report that the reciprocal mutant in D2 receptor restores receptor‐dependent phosphorylation of ERK1/2 and activation of Kir3.0 channels indicating a receptor specific effect of the conserved residues. This work is supported by NIP grant from the AACP.