| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T13795 | ||||
| Target Name | Neuronal acetylcholine receptor subunit alpha-9 | ||||
| Target Type | Research |
||||
| Drug Potency against Target | ACV-1 | Drug Info | IC50 = 19 nM | ||
| Action against Disease Model | ACV-1 | Stable MDA-MB-231 breast cancer cell lines were established in which expression of the alpha9-nAChR subunit was inhibited using short interfering RNA. MCF-10A normal h uMan breast epithelial cells were established in which the alpha9-nAChR subunit could be conditionally overexpressed by removal of doxycycline from the culture fluid. Cell proliferation and soft agar assays and t uMor growth in nude mice were used as measures of cell transformation. All statistical tests were two-sided. | [553068] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Alpha-conotoxins Vc1.1 and RgIA are peptides from the venom of marine Conus snails that are currently in development as a treatment for neuropathic pain. We have reported previously that the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) selective-conotoxins Vc1.1 and RgIA potently and selectively inhibit high voltage-activated (HVA) N-type calci uM channel currents in dissociated neurons from rat dorsal root ganglia (DRG). Our data indicated that Vc1.1 does not interact directly with N-type Ca(2+) channels but inhibits them via GABA(B) receptor activation. The present study investigated Vc1.1 and RgIA inhibition of N-type Ca(2+) channels currents in DRG neurons of wild-type and alpha9 knockout (KO) mice to determine if the alpha9 nAChR was necessary for inhibition of the Ca(2+) channel current. Application of Vc1.1 (100 nM) inhibited N-type Ca(2+) channel currents to 69.2 +/- 3.5% of control in DRG neurons isolated from wild-type mice. In >70% of DRG neurons isolated from the alpha9 KO mice, both Vc1.1 and RgIA selectively inhibited N-type Ca(2+) channel currents with an IC(50) of 24.6 nM and 22.4 nM, respectively. The GABA(B) receptor antagonist CGP55845 (1 microM) antagonized the effect of Vc1.1 and RgIA on the N-type calci uM channels in alpha9 KO mice. RT-PCR and western blot analysis confirmed the absence of the alpha9 nAChR in mice carryinga null mutation for the nAChR alpha9 gene. These results demonstrate that the inhibition of N-type Ca(2+) channel channels by Vc1.1 and RgIA is not mediated by the expression of alpha9alpha10 nAChRs in DRG neurons. | ||||
| References | |||||
| Ref 553068 | Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells. J Natl Cancer Inst. 2010 Sep 8;102(17):1322-35. doi: 10.1093/jnci/djq300. Epub 2010 Aug 23. | ||||
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