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Cytoplasmic tail of D1 dopaminergic receptor differentially regulates desensitization and phosphorylation by G protein-coupled receptor kinase 2 and 3.

Authors: Sedaghat, K  Tiberi, M 
Citation: Sedaghat K and Tiberi M, Cell Signal. 2011 Jan;23(1):180-92. Epub 2010 Sep 17.
Pubmed: (View Article at PubMed) PMID:20837135
DOI: Full-text: DOI:10.1016/j.cellsig.2010.09.002

Herein, we investigate the differential D1 dopaminergic receptor (D1R) regulation by G protein-coupled receptor kinase (GRK) 2 and 3 using two truncated receptors lacking the distal (Delta425) and distal-central (Delta379) cytoplasmic tail (CT) regions. We first show the association between D1R and GRKs in co-transfected cells and rat striatum. Our studies further indicate that deletion of distal CT region of D1R does not alter the association between receptor and GRK2. Meanwhile, removal of both distal and central CT regions culminates in a drastic increase in the basal association between Delta379 and GRK2 relative to D1R and Delta425. Interestingly, CT truncations have no effect on the basal and DA-induced association of receptors with GRK3. Furthermore, we demonstrate that desensitization of D1R is considerably more robust in cells expressing GRK3. Notably, the robust GRK3-induced D1R desensitization is not attenuated by CT deletions. However, GRK2-induced Delta425 desensitization is not detectable whereas we unexpectedly find that Delta379 desensitization is similar to GRK2-induced D1R desensitization. GRK2 and GRK3-dependent desensitization of wild type D1R is not linked to differences in the extent of DA-induced receptor phosphorylation. Moreover, our studies show that GRK2-induced D1R phosphorylation is only modulated by deletion of distal CT region while distal and central CT regions control GRK3-induced D1R phosphorylation. Intriguingly, dopamine-induced Delta379 phosphorylation by GRK3 was significantly lower than receptor phosphorylation in cells harboring Delta379 alone or Delta379 and GRK2. Overall, our study suggests an intricate interplay between CT regions of D1R in differentially regulating receptor responsiveness by GRK2 and GRK3.

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CRRD Object Information
CRRD ID: 5685022
Created: 2012-01-09
Species: All species
Last Modified: 2012-01-09
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.