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PMID: 2436701 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Prostacyclin analogues reduce ADP-ribosylation of the alpha-subunit of the regulatory Gs-protein and diminish adenosine (A2) responsiveness of platelets.

British journal of pharmacology ·Vol. 90 ·No. 3 ·1987-03-00 ·Pages 501-10

Edwards RJ, MacDermot J, Wilkins AJ

Abstract

Prostacyclin and adenosine activate adenylate cyclase in human platelet membranes and inhibit platelet aggregation. Results are presented which show that prolonged incubation of platelets with iloprost (a stable prostacyclin analogue) results in a reduction in the capacity for adenylate cyclase activation by the adenosine analogue 5'-(N-ethyl)-carboxamidoadenosine (NECA), NaF, guanyl-5'-yl imidodiphosphate or GTP. However, iloprost pretreatment resulted in no change in the binding of [3H]-NECA to platelet membranes. These results contrast with those obtained after pretreatment with 2-chloroadenosine which revealed no change in NaF or guanyl-5'-yl imidodiphosphate sensitivity of adenylate cyclase. Pretreatment with 2-chloroadenosine resulted in reduced NECA-dependent adenylate cyclase activation, and loss of [3H]-NECA binding sites. The heterologous desensitization of adenosine A2-receptors by iloprost is accompanied by a loss (greater than 80%) of a 45 kDa protein from the plasma membrane, as revealed by [32P]-ADP-ribosylation in the presence of cholera toxin. It is proposed that this example of heterologous desensitization is mediated by elimination of Gs alpha, a subunit of the stimulatory guanyl nucleotide-binding regulatory protein.

MeSH Terms
2-Chloroadenosine Adenosine/analogs & derivatives,pharmacology Adenosine Diphosphate Ribose/biosynthesis Adenosine-5'-(N-ethylcarboxamide) Adenylyl Cyclases/blood Adult Blood Platelets/drug effects,metabolism Epoprostenol/analogs & derivatives,pharmacology GTP-Binding Proteins/metabolism Guanylyl Imidodiphosphate/pharmacology Humans Iloprost In Vitro Techniques Sodium Fluoride/pharmacology Vasodilator Agents/pharmacology
Chemicals
Vasodilator Agents 2-Chloroadenosine Adenosine Diphosphate Ribose Guanylyl Imidodiphosphate Adenosine-5'-(N-ethylcarboxamide) Sodium Fluoride Epoprostenol GTP-Binding Proteins Adenylyl Cyclases Iloprost Adenosine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Edwards R J
MacDermot J
Wilkins A J
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44 references, click to expand
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1111/j.1476-5381.1987.tb11199.x
Published
1987-03-00
Pages
501-10
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1917175
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1476-5381.1987.tb11199.x PMC Full Text View journal details
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