Abstract
The dopamine D2 receptor and D3 receptor (D2R, D3R) have high homology in both their amino acid composition and signaling pathways. Virtually all signaling pathways reported thus far overlap between the two receptors with the exception that the D3R signals are 2∼5 times less efficient than D2R. Previous studies have suggested that conformational constraints of D3R might be responsible for the poor coupling with the G protein. To this hypothesis, point mutations were introduced into some of the conserved regions between D2R and D3R, and their effects on receptor expression were investigated. Among the four conserved intracellular receptor regions examined (TTT motif in the 1st intracellular loop, SS motif in the 2nd intracellular loop, YxxL and TxxS/xS motifs in the 3rd intracellular loop), a mutation of the Thr-Thr-Thr (TTT) motif in the first intracellular loop or the LxxY motif in the 3rd intracellular loop markedly decreased the level of D3R expression compared with D2R. The TTT motif was further mutated individually or in combination to test which residue plays a critical role on the expression of the receptor proteins. Different amino acids between D2R and D3R in the 1st intracellular loop were exchanged to determine if the adjacent amino acid residues are responsible for the differences between D2R and D3R. The first two threonine residues become more important when the individual threonine residue is mutated. However, all three intact threonine residues are essential for proper expression of the receptor proteins. The neighboring sequences around the triplet threonine residues in the 1st loop of D3R are not important for proper positioning of the receptor proteins on the plasma membrane. It was concluded that D2R has a more flexible overall conformation that can accept mutated residues in the intracellular region than D3R, which might be partly responsible for the quantitative differences in the signaling efficiency between D2R and D3R.
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Cho, EY., Park, J.H. & Kim, KM. Roles of conserved intracellular sequences regions for the proper expression of dopamine D2 and D3 receptors. Arch. Pharm. Res. 31, 634–639 (2008). https://doi.org/10.1007/s12272-001-1205-6
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DOI: https://doi.org/10.1007/s12272-001-1205-6