QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.032722v1 71/5/1349    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Related articles in MolPharm Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lane, J. R. Articles by Milligan, G. Search for Related Content PubMed PubMed Citation Articles by Lane, J. R. Articles by Milligan, G.

Protean Agonism at the Dopamine D₂ Receptor: (S)-3-(3-Hydroxyphenyl)-N-propylpiperidine Is an Agonist for Activation of G_o1 but an Antagonist/Inverse Agonist for G_i1,G_i2, and G_i3

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (J.R.L., G.M.); and Screening & Compound Profiling, GlaxoSmithKline Research & Development, Harlow, Essex, United Kingdom (A.W., S.R., B.P.)

A range of ligands displayed agonism at the long isoform of the human dopamine D₂ receptor, whether using receptor-G protein fusions or membranes of cells in which pertussis toxin-resistant mutants of individual G_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 [³⁵S]GTPS onto each of G_i1,G_i2,G_i3, and G_o1. By contrast, (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine was a partial agonist when G_o1 was the target G protein but an antagonist/inverse agonist at G_i1,G_i2, and G_i3. In ligand binding assays, dopamine identified both high- and low-affinity states at each of the dopamine D₂ 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 D₂ receptor was fused to G_i1,G_i2, or G_i3. However, it bound to distinct high- and low-affinity states of the D₂ receptor-G_o1 fusion, with the high-affinity state being eliminated by guanine nucleotide. Likewise, although dopamine identified guanine nucleotide-sensitive high-affinity states of the D₂ receptor when expression of pertussis toxin-resistant forms of each of G_i1, G_i2, G_i3, and G_o1 was induced, (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine identified a high-affinity site only in the presence of G_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 D₂ receptor and may explain in vivo actions of this ligand.

Address correspondence to: Dr. G. Milligan, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K. E-mail: g.milligan{at}bio.gla.ac.uk

Related articles in MolPharm:

Missing Links: Mechanisms of Protean Agonism

Richard R. Neubig
MolPharm 2007 71: 1200-1202. [Abstract] [Full Text]  

This article has been cited by other articles:

				L. Zhang, L. F. Brass, and D. R. Manning The Gq and G12 Families of Heterotrimeric G Proteins Report Functional Selectivity Mol. Pharmacol., January 1, 2009; 75(1): 235 - 241. [Abstract] [Full Text] [PDF]

				L. A. Stoddart, N. J. Smith, L. Jenkins, A. J. Brown, and G. Milligan Conserved Polar Residues in Transmembrane Domains V, VI, and VII of Free Fatty Acid Receptor 2 and Free Fatty Acid Receptor 3 Are Required for the Binding and Function of Short Chain Fatty Acids J. Biol. Chem., November 21, 2008; 283(47): 32913 - 32924. [Abstract] [Full Text] [PDF]

				J. R. Lane, D. Henderson, B. Powney, A. Wise, S. Rees, D. Daniels, C. Plumpton, I. Kinghorn, and G. Milligan Antibodies that identify only the active conformation of Gi family G protein {alpha} subunits FASEB J, June 1, 2008; 22(6): 1924 - 1932. [Abstract] [Full Text] [PDF]

				M. Canals and G. Milligan Constitutive Activity of the Cannabinoid CB1 Receptor Regulates the Function of Co-expressed Mu Opioid Receptors J. Biol. Chem., April 25, 2008; 283(17): 11424 - 11434. [Abstract] [Full Text] [PDF]

				J. R. Lane, B. Powney, A. Wise, S. Rees, and G. Milligan G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 319 - 330. [Abstract] [Full Text] [PDF]

				M. J. Millan, C. M. la Cour, F. Novi, R. Maggio, V. Audinot, A. Newman-Tancredi, D. Cussac, V. Pasteau, J.-A. Boutin, T. Dubuffet, et al. S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 587 - 599. [Abstract] [Full Text] [PDF]