ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor
Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an agonist for activation of Go1 but an antagonist/inverse agonist for Gi1,Gi2, and Gi3
Lane, J Robert; Powney, Ben; Wise, Alan; Rees, Steven; Milligan, Graeme
Authors
Ben Powney
Alan Wise
Steven Rees
Graeme Milligan
Abstract
A range of ligands displayed agonism at the long isoform of the human dopamine D(2) receptor, whether using receptor-G protein fusions or membranes of cells in which pertussis toxin-resistant mutants of individual Galpha(i)-family G proteins could be expressed in an inducible fashion. Varying degrees of efficacy were observed for individual ligands as monitored by their capacity to load [(35)S]GTPgammaS onto each of Galpha(i1),Galpha(i2),Galpha(i3), and Galpha(o1). By contrast, (S)-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine was a partial agonist when Galpha(o1) was the target G protein but an antagonist/inverse agonist at Galpha(i1),Galpha(i2), and Galpha(i3). In ligand binding assays, dopamine identified both high- and low-affinity states at each of the dopamine D(2) receptor-G protein fusion proteins, and the high-affinity state was eliminated by guanine nucleotide. (S)-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine bound to an apparent single state of the constructs in which the D(2) receptor was fused to Galpha(i1),Galpha(i2), or Galpha(i3). However, it bound to distinct high- and low-affinity states of the D(2) receptor-Galpha(o1) fusion, with the high-affinity state being eliminated by guanine nucleotide. Likewise, although dopamine identified guanine nucleotide-sensitive high-affinity states of the D(2) receptor when expression of pertussis toxin-resistant forms of each of Galpha(i1), Galpha(i2), Galpha(i3), and Galpha(o1) was induced, (S)-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine identified a high-affinity site only in the presence of Galpha(o1). p-Tyramine displayed a protean ligand profile similar to that of (S)-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine but with lower potency. These results demonstrate (S)-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine to be a protean agonist at the D(2) receptor and may explain in vivo actions of this ligand.
Citation
Lane, J. R., Powney, B., Wise, A., Rees, S., & Milligan, G. (2007). Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an agonist for activation of Go1 but an antagonist/inverse agonist for Gi1,Gi2, and Gi3. Molecular Pharmacology, 71(5), 1349-1359. https://doi.org/10.1124/mol.106.032722
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 7, 2007 |
Online Publication Date | Apr 25, 2007 |
Publication Date | May 1, 2007 |
Deposit Date | Apr 22, 2020 |
Journal | Molecular Pharmacology |
Print ISSN | 0026-895X |
Publisher | American Society for Pharmacology and Experimental Therapeutics |
Peer Reviewed | Peer Reviewed |
Volume | 71 |
Issue | 5 |
Pages | 1349-1359 |
DOI | https://doi.org/10.1124/mol.106.032722 |
Public URL | http://molpharm.aspetjournals.org/cgi/doi/10.1124/mol.106.032722 |
Publisher URL | http://molpharm.aspetjournals.org/content/71/5/1349 |
You might also like
Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10
(2021)
Journal Article
GRKs as Key Modulators of Opioid Receptor Function
(2020)
Journal Article
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: digital-library-support@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search