Suramin Disrupts Receptor-G Protein Coupling by Blocking Association of G Protein α and βγ Subunits
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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Suramin disrupts GPCR binding with the G protein by blocking the association of G protein α and βγ subunits.
“Suramin disrupts GPCR binding with the G protein by blocking the association of G protein α and βγ subunits [28].”
From G-protein-coupled receptor participates in 20-hydroxyecdysone signaling on the plasma membrane (2014) · cites this paper as [28]
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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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