Loading...
Please wait, while we are loading the content...
Similar Documents
Inverse agonist activity of selected ligands of platelet-activating factor receptor.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dupré, Denis J. Gouill, Christian Le Rola-Pleszczynski, Marek Stankova, Jana |
| Copyright Year | 2001 |
| Abstract | The receptor for platelet-activating factor (PAFR) is a member of the G protein-coupled receptor (GPCR) family. According to the allosteric ternary complex model, GPCRs exist in an equilibrium between different conformations. Agonist binding promotes and stabilizes the receptor in an active conformation. On the other hand, ligands that stabilize the inactive conformation are known as inverse agonists. Due to the association of platelet-activating factor (PAF) with diverse physiological and pathological processes, considerable efforts have been invested in the development of antagonists to PAFR. A large number of these molecules has been shown to specifically interact with PAFR but, surprisingly, little is known about their impact on the conformation of the receptor and its activity. By using a constitutively active mutant (L231R) of the human PAFR and by transiently coexpressing the wild-type (WT) receptor with the G(alpha)q subunit of the trimeric G protein, we were able to address this issue with ligands of diverse structures such as phospholipids, benzodiazepines, furans, and others. We demonstrated that some of these molecules are potent inverse agonists. For example, when cells (WT PAFR + G(alpha)q) were exposed to WEB2086, SM10661, or alprazolam, the basal inositol phosphate production was reduced by 53 +/- 6, 44 +/- 3, and 54 +/- 4%, respectively. The decrease in basal inositol phosphate production by WEB2086 was significantly inhibited by a more neutral antagonist BN52021, confirming the specificity of the reaction. We demonstrate here that WEB2086 and other known ligands previously considered as antagonists can act as inverse agonists on the human PAF receptor. |
| File Format | PDF HTM / HTML |
| PubMed reference number | 11561099 |
| Journal | Medline |
| Volume Number | 299 |
| Issue Number | 1 |
| Alternate Webpage(s) | http://jpet.aspetjournals.org/content/jpet/299/1/358.full.pdf |
| Journal | The Journal of pharmacology and experimental therapeutics |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
