| Autor: |
Pauwels, P. J., Wurch, T., Tardif, S., Finana, F., Colpaert, F. C. |
| Předmět: |
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| Zdroj: |
Naunyn-Schmiedeberg's Archives of Pharmacology; May2001, Vol. 363 Issue 5, p526-536, 11p |
| Abstrakt: |
Variations in the measurement of ligand's intrinsic activity between receptor subtypes is a common consequence of unequal receptor:G protein density ratios. We have investigated ligand activation at the α2-adrenoceptor (α2-AR) subtypes under defined expression conditions of one receptor molecule for one Gα protein molecule using fusion proteins. Fusion between either a wt α2C AR or a mutant Thr381Lys α2C AR and a chimeric Gαq/i1 protein displayed robust, transient (-)-adrenaline-mediated Ca2+ responses with similar potencies (pEC50: 7.78 and 7.66) and kinetic properties. A comparison of the intrinsic activities of α2 AR agonists found d-medetomidine to be the only compound with an efficacy similar to that of (-)-adrenaline. The Ca2+ responses as mediated by UK 14304, oxymetazoline and clonidine became more potent and efficacious at the Thr381Lys α2C AR, whereas the response as mediated by talipexole displayed a higher potency with an unaltered maximal response. Whereas only small differences in ligand's intrinsic activities between the wt α2A, α2B and α2C AR fusion proteins were observed with most ligands, oxymetazoline was virtually silent at the α2A AR while active as a partial and apparently full agonist at the α2C AR and α2B AR, respectively. The mutant α2 AR subtypes could be differentiated using the apparent positive efficacy of ligands that used to be defined as antagonists. The following rank order of maximal responses was observed for the Thr381Lys α2C AR: idazoxan ≃ SKF 86466 > atipamezole >> dexefaroxan; Thr373Lys α2A AR: SKF 86466 > idazoxan = atipamezole > dexefaroxan; and Thr370Lys α2B AR: atipamezole > idazoxan ≃ dexefaroxan. RX 811059 (10 µM) was the only compound to be completely silent at both the wt and mutant α2 AR subtypes. In conclusion, silent α2 AR ligands are probably rare in these specified α2 AR systems. Most antagonists may actually possess partial agonist properties at the α2 AR subtypes, which are facilitated by the same mutation in the distal portion of their third intracellular loop. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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