title: Suramin disrupts receptor-G protein coupling by blocking association of G protein alpha and betagamma 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chung
authors.forename: John C
authors.initials: JC
authors.lastname: Kermode
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003432:Cross-Linking Reagents; D020558:GTP Phosphohydrolases / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000037:antagonists & inhibitors*; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors*; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology*
chemical_list: D003432:Cross-Linking Reagents; C118981:G-protein Beta gamma; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D043562:Receptors, G-Protein-Coupled; D018005:Receptors, Vasoactive Intestinal Peptide; D011994:Recombinant Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013498:Suramin; D020558:GTP Phosphohydrolases