| Autor: |
Briggs, Clark A., Gubbins, Earl J., Marks, Michael J., Putman, C. Brent, Thimmapaya, Rama, Meyer, Michael D., Surowy, Carol S. |
| Zdroj: |
Molecular Pharmacology; July 2006, Vol. 70 Issue: 1 p227-240, 14p |
| Abstrakt: |
α4β2 nicotinic acetylcholine receptors (nAChRs) are recognized as the principal nicotine binding site in brain. Recombinant α4β2 nAChR demonstrate biphasic concentration-response relationships with low- and high-EC50components. This study shows that untranslated regions (UTR) can influence expression of high-sensitivity subforms of α4β2 and α3β2 nAChR. Oocytes injected with α4 and β2 RNA lacking UTR expressed biphasic concentration-response relationships for acetylcholine with high-sensitivity EC50values of 0.5 to 2.5 μM (14–24% of the population) and low-sensitivity EC50values of 110 to 180 μM (76–86%). In contrast, message with UTR expressed exclusively the high-sensitivity α4β2 nAChR subform with an acetylcholine EC50value of 2.2 μM. Additional studies revealed pharmacological differences between high- and low-sensitivity α4β2 subforms. Whereas the antagonists dihydro-β-erythroidine (IC50of 3–6 nM) and methyllycaconitine (IC50of 40–135 nM) were not selective between high- and low-sensitivity α4β2, chlorisondamine, mecamylamine, and d-tubocurarine were, respectively, 100-, 8-, and 5-fold selective for the α4β2 subform with low sensitivity to acetylcholine. Conversely, agonists that selectively activated the high-sensitivity α4β2 subform with respect to efficacy as well as potency were identified. Furthermore, two of these agonists were shown to activate mouse brain α4β2 as well as the ferret high-sensitivity α4β2 expressed in Xenopus laevisoocytes. With the use of UTR-containing RNA, exclusive expression of a novel high-sensitivity α3β2 nAChR was also achieved. These studies 1) provide further evidence for the existence of multiple subforms of α4β2 nAChR, 2) extend that to α3β2 nAChR, 3) demonstrate UTR influence on β2-containing nAChR properties, and 4) reveal compounds that interact with α4β2 in a subform-selective manner. |
| Databáze: |
Supplemental Index |
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