UB-165: A novel nicotinic agonist with subtype selectivity implicates the alpha 4 beta 2*subtype in the modulation of dopamine release from rat striatal synaptosomes
Sharples, C. G. V., Kaiser, S., Soliakov, L., Marks, M. J., Collins, A. C., Washburn, M., Wright, E., Spencer, J. A., Gallagher, T., Whiteaker, P. and Wonnacott, S., 2000. UB-165: A novel nicotinic agonist with subtype selectivity implicates the alpha 4 beta 2*subtype in the modulation of dopamine release from rat striatal synaptosomes. Journal of Neuroscience, 20 (8), pp. 2783-2791.
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Presynaptic nicotinic acetylcholine receptors (nAChRs) on striatal synaptosomes stimulate dopamine release. Partial inhibition by the alpha 3 beta 2-selective alpha-conotoxin-MII indicates heterogeneity of presynaptic nAChRs on dopamine terminals. We have used this alpha-conotoxin and UB-165, a novel hybrid of epibatidine and anatoxin-a, to address the hypothesis that the alpha-conotoxin-MII-insensitive subtype is composed of alpha 4 and beta 2 subunits. UB-165 shows intermediate potency, compared with the parent molecules, at alpha 4 beta 2* and alpha 3-containing binding sites, and resembles epibatidine in its high discrimination of these sites over alpha 7-type and muscle binding sites. (+/-)-Epibatidine, (+/-)-anatoxin-a, and (+/-)-UB-165 stimulated [H-3]-dopamine release from striatal synaptosomes with EC50 values of 2.4, 134, and 88 nM, and relative efficacies of 1:0.4:0.2, respectively. alpha-Conotoxin-MII inhibited release evoked by these agonists by 48, 56, and 88%, respectively, suggesting that (+/-)- UB-165 is a very poor agonist at the alpha-conotoxin-MII-insensitive nAChR subtype. In assays of Rb-86(+) efflux from thalamic synaptosomes, a model of an alpha 4 beta 2* nAChR response, (+/-)- UB-165 was a very weak partial agonist; the low efficacy of (+/-)-UB-165 at alpha 4 beta 2 nAChR was confirmed in Xenopus oocytes expressing various combinations of human nAChR subunits. In contrast, (+/-)- UB-165 and (+/-)-anatoxin-a were similarly efficacious and similarly sensitive to alpha-conotoxin-MII in increasing intracellular Ca2+ in SH-SY5Y cells, a functional assay for native alpha 3-containing nAChR. These data support the involvement of alpha 4 beta 2* nAChR in the presynaptic modulation of striatal dopamine release and illustrate the utility of exploiting a novel partial agonist, together with a selective antagonist, to dissect the functional roles of nAChR subtypes in the brain.
|Creators||Sharples, C. G. V., Kaiser, S., Soliakov, L., Marks, M. J., Collins, A. C., Washburn, M., Wright, E., Spencer, J. A., Gallagher, T., Whiteaker, P. and Wonnacott, S.|
|Departments||Faculty of Science > Biology & Biochemistry|
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