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| Content Provider | PubMed Central |
|---|---|
| Author | Charles, Parnot Bardin, Sabine Miserey-lenkei, Stéphanie Denis, Guedin Pierre, Corvol Clauser, Eric |
| Copyright Year | 2000 |
| Abstract | The constitutive activation of G-protein-coupled receptors is a major new approach to investigating their physiopathology and pharmacology. A large number of spontaneous and site-directed mutations resulting in constitutive activity have been identified, but systematic mapping of the amino acids involved for a given receptor would be extremely useful for complete elucidation of the molecular mechanisms underlying its activation. We carried out such mapping for the angiotensin II type 1A (AT1A) receptor by screening a randomly mutated cDNA library after expressing the mutated clones in eukaryotic cells. To test the AT1A mutants generated, we developed an original, specific, and highly sensitive assay based on the properties of CGP42112A. This classical AT2 agonist is a weak partial agonist of the wild-type AT1A receptor and becomes a full agonist for constitutively active AT1A mutants, as shown experimentally and in allostery-based theoretical models. Activation of the mutated receptors by CGP42112A was monitored by using the bioluminescent protein æquorin, a very sensitive and specific sensor of intracellular calcium mobilization. The screening of 4,800 clones, providing an exhaustive coverage of all of the mutations generated, led to the identification of 16 mutations in sequences encoding the transmembrane domains that were responsible for high sensitivity to CGP42112A. The constitutive activity was confirmed by agonist-independent production of inositol phosphates, which showed that at least half of the clones had significantly increased basal activity. These data demonstrate that this new type of approach is very efficient for the systematic identification of constitutively active mutants of G-protein-coupled receptors. |
| Related Links | http://dx.doi.org/10.1073/pnas.110142297 |
| Ending Page | 7620 |
| Page Count | 6 |
| Starting Page | 7615 |
| File Format | |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 13 |
| Volume Number | 97 |
| Language | English |
| Publisher | The National Academy of Sciences |
| Publisher Date | 2000-06-20 |
| Access Restriction | Open |
| Rights Holder | The National Academy of Sciences |
| Subject Keyword | General Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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