MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Waldhoer, M.
Right arrow Articles by Nanoff, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Waldhoer, M.
Right arrow Articles by Nanoff, C.

Vol. 53, Issue 5, 808-818, May 1998

Differential Uncoupling of A1 Adenosine and D2 Dopamine Receptors by Suramin and Didemethylated Suramin (NF037)

Maria Waldhoer, Elisa Bofill-Cardona, Graeme Milligan, Michael Freissmuth, and Christian Nanoff

Institute of Pharmacology, Vienna University, A-1090 Vienna, Austria (M.W., E.B.-C., M.F., C.N.), and Institute of Biomedical and Life Sciences, Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, UK (G.M.)

Suramin analogues uncouple two Gi/Go-coupled receptors, the D2 dopamine receptor in rat striatum and the A1 adenosine receptor in human cerebral cortex, with distinct structure-activity relations. This discrepancy may reflect true differences in the affinity of the analogues for specific receptor/G protein complexes or may be attributable to differences in species or in the tissue source used. We addressed this question by using human embryonic kidney 293 cells that stably express the human A1 and rat A1 receptor and the human D2 receptor. Suramin is 10-fold more potent than its didemethylated analogue NF037 in inhibiting the interaction between G proteins and the rat A1 or human A1 receptor; in contrast, both compounds are equipotent in uncoupling the D2 receptor. These differences are observed regardless of whether (1) inhibition of high affinity agonist binding to the receptors or (2) agonist-stimulated GTPgamma S binding is used as readout, (3) the receptors are allowed to interact with the G protein complement in human embryonic kidney 293 cell membranes, or (4) the receptors are forced to interact with a defined G protein alpha  subunit (i.e., after reconstituting pertussis toxin-treated membranes with exogenous rGialpha -1). The apparent affinity of suramin depends in a linear manner on receptor occupancy, which shows that suramin and the receptor compete for the G protein. Finally, the affinity of the receptors for rGialpha -1 (human A1 > rat A1 > human D2) is inversely correlated with the potency of suramin in uncoupling ternary complexes formed by these receptors and thus determines the selectivity of the suramin analogues for specific receptor/G protein tandems.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
V. Verma, A. Mann, W. Costain, G. Pontoriero, J. M. Castellano, K. Skoblenick, S. K. Gupta, Z. Pristupa, H. B. Niznik, R. L. Johnson, et al.
Modulation of Agonist Binding to Human Dopamine Receptor Subtypes by L-Prolyl-L-leucyl-glycinamide and a Peptidomimetic Analog
J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1228 - 1236.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
E. Kostenis, L. Martini, J. Ellis, M. Waldhoer, A. Heydorn, M. M. Rosenkilde, P. K. Norregaard, R. Jorgensen, J. L. Whistler, and G. Milligan
A Highly Conserved Glycine within Linker I and the Extreme C Terminus of G Protein {alpha} Subunits Interact Cooperatively in Switching G Protein-Coupled Receptor-to-Effector Specificity
J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 78 - 87.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Pankevych, V. Korkhov, M. Freissmuth, and C. Nanoff
Truncation of the A1 Adenosine Receptor Reveals Distinct Roles of the Membrane-proximal Carboxyl Terminus in Receptor Folding and G Protein Coupling
J. Biol. Chem., August 8, 2003; 278(32): 30283 - 30293.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
E. Breitweg-Lehmann, C. Czupalla, R. Storm, O. Kudlacek, W. Schunack, M. Freissmuth, and B. Nurnberg
Activation and Inhibition of G Proteins by Lipoamines
Mol. Pharmacol., March 1, 2002; 61(3): 628 - 636.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
F. Roka, L. Brydon, M. Waldhoer, A. D. Strosberg, M. Freissmuth, R. Jockers, and C. Nanoff
Tight Association of the Human Mel1a-Melatonin Receptor and Gi: Precoupling and Constitutive Activity
Mol. Pharmacol., November 1, 1999; 56(5): 1014 - 1024.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
M. Waldhoer, A. Wise, G. Milligan, M. Freissmuth, and C. Nanoff
Kinetics of Ternary Complex Formation with Fusion Proteins Composed of the A1-Adenosine Receptor and G Protein alpha -Subunits
J. Biol. Chem., October 22, 1999; 274(43): 30571 - 30579.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. G. Seidel, M. Klinger, M. Freissmuth, and C. Holler
Activation of Mitogen-activated Protein Kinase by the A2A-adenosine Receptor via a rap1-dependent and via a p21ras-dependent Pathway
J. Biol. Chem., September 3, 1999; 274(36): 25833 - 25841.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Bofill-Cardona, O. Kudlacek, Q. Yang, H. Ahorn, M. Freissmuth, and C. Nanoff
Binding of Calmodulin to the D2-Dopamine Receptor Reduces Receptor Signaling by Arresting the G Protein Activation Switch
J. Biol. Chem., October 13, 2000; 275(42): 32672 - 32680.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
O. El Far, E. Bofill-Cardona, J. M. Airas, V. O'Connor, S. Boehm, M. Freissmuth, C. Nanoff, and H. Betz
Mapping of Calmodulin and Gbeta gamma Binding Domains within the C-terminal Region of the Metabotropic Glutamate Receptor 7A
J. Biol. Chem., August 10, 2001; 276(33): 30662 - 30669.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics