Cited by 59Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingNeuropeptides and Animal Physiology

Suramin Disrupts Receptor-G Protein Coupling by Blocking Association of G Protein α and βγ Subunits

Chung, Wen-Cheng, Kermode, John C.·2005·The Journal of Pharmacology and Experimental Therapeutics

Abstract

Most drugs target a receptor for a hormone or neurotransmitter. A newer strategy for drug development is to target a downstream signaling element, such as the G protein associated with a receptor. Suramin is considered a lead compound targeting this moiety. It inhibits binding of guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) to G proteins and reduces agonist binding to G protein-coupled receptors. Suramin is thought to uncouple the G protein from its associated receptor, although there is no direct evidence for this mechanism. We have now examined the effect of suramin on G protein signaling for the vasoactive intestinal peptide (VIP) receptor in lung. The primary experimental strategy was a two-step cross-linking reaction that covalently captures the VIP-receptor-G protein ternary complex. Such cross-linking provided the first direct evidence that suramin physically disrupts receptor-G protein coupling. We investigated how this uncoupling relates to the inhibition of GTPgammaS binding. Suramin indiscriminately hindered the dissociation of various guanine nucleotides from the G protein, implying that its action is not allosteric. Further cross-linking studies suggested that suramin does not obstruct the receptor docking site directly but appears to block the interface between G protein alpha and betagamma subunits. Observations with a purified system of recombinant G protein subunits without a receptor yielded direct evidence that suramin suppresses the association between these subunits. This action can explain how it both disrupts receptor-G protein coupling and inhibits guanine nucleotide release. The improved understanding of suramin's action advances the development of selective inhibitors of G protein signaling.

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Crossref · 10.1124/jpet.104.078311

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Authors
Chung, W.-C., & Kermode, J. C.
Affiliations
University of Mississippi Medical Center (US)
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2005-04
Volume
313
Issue
1
Pages
191-198
ISSN
0022-3565 (ISSN-L)
OpenAlex
W2120179926
Cited by
59
References
41
Citations by year
2025: 2 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 5 · 2012: 1
FWCI
1.76
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
suramin, G protein signaling, receptor-G protein uncoupling, vasoactive intestinal peptide receptor, allosteric inhibition
MeSH terms
Animals, Binding, Competitive, Cross-Linking Reagents, Kinetics, Lung, Male, Recombinant Proteins, Suramin, Guanosine 5'-O-(3-Thiotriphosphate), Rats, Sprague-Dawley, Receptors, Vasoactive Intestinal Peptide, GTP Phosphohydrolases, Receptors, G-Protein-Coupled, GTP-Binding Protein alpha Subunits, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Rats, In Vitro Techniques

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