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G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors

Lane, J R; Powney, B; Wise, A; Rees, S; Milligan, G

Authors

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

B Powney

A Wise

S Rees

G Milligan



Abstract

The human dopamine D2L receptor couples promiscuously to multiple members of the Gαi/o subfamily. Despite the high homology of the D2L and D3 receptors, the G protein coupling specificity of the human D3 receptor is less clearly characterized. The primary aim of this study, then, was the parallel characterization of the G protein coupling specificity of the D2L and D3 receptors. By using both receptor-G protein fusion proteins and stable cell lines in which pertussis toxin-resistant mutants of individual Gαi-family G proteins were expressed in an inducible fashion, we demonstrated highly selective coupling of the D3 receptor to Gαo1. Furthermore, by using the fusion proteins to ensure identical stoichiometry of receptor to G protein for each pairing, a range of ligands displayed higher potency and, for partial agonists, higher efficacy at the D3 receptor when coupled to Gαo1 compared with the D2L receptor. The second aim of this study was to investigate the molecular basis of the above differential G protein coupling specificity. The importance of a 12-amino acid sequence from the C-terminal end of the third intracellular loop of the D2L receptor in providing promiscuity in G protein coupling was demonstrated using a chimeric D3/D2 receptor in which the equivalent region of the D3 receptor was exchanged for this sequence. This chimera displayed D3-like affinity for [3H]spiperone and potency for agonists but gained D2-like ability to couple to each of Gαi1–3 as well as Gαo1.

Citation

Lane, J. R., Powney, B., Wise, A., Rees, S., & Milligan, G. (2008). G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors. Journal of Pharmacology and Experimental Therapeutics, 325(1), 319-330. https://doi.org/10.1124/jpet.107.134296

Journal Article Type Article
Acceptance Date Jan 23, 2008
Online Publication Date Mar 17, 2008
Publication Date 2008-04
Deposit Date Apr 22, 2020
Journal Journal of Pharmacology and Experimental Therapeutics
Print ISSN 0022-3565
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 325
Issue 1
Pages 319-330
DOI https://doi.org/10.1124/jpet.107.134296
Public URL http://jpet.aspetjournals.org/cgi/doi/10.1124/jpet.107.134296
Publisher URL http://jpet.aspetjournals.org/content/325/1/319