| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T21434 | ||||
| Target Name | Neuronal acetylcholine receptor subunit alpha-10 | ||||
| Target Type | Clinical Trial |
||||
| 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 | Efferent inhibition of cochlear hair cells is mediated by alpha9alpha10 nicotinic cholinergic receptors (nAChRs) functionally coupled to calci uM-activated, small conductance (SK2) potassi uM channels. Before the onset of hearing, efferent fibers transiently make functional cholinergic synapses with inner hair cells (IHCs). The retraction of these fibers after the onset of hearing correlates with the cessation of transcription of the Chrna10 (but not the Chrna9) gene in IHCs. To further analyze this developmental change, we generated a transgenic mice whose IHCs constitutively express alpha10 into adulthood by expressing the alpha10 cDNA under the control of the Pou4f3 gene promoter. In situ hybridization showed that the alpha10 mRNA is expressed in IHCs of 8-week-old transgenic mice, but not in wild-type mice. Moreover, this mRNA is translated into a functional protein, since IHCs from P8-P10 alpha10 transgenic mice backcrossed to a Chrna10(-/-) background (whose IHCs have no cholinergic function) displayed normal synaptic and acetylcholine (ACh)-evoked currents in patch-clamp recordings. Thus, the alpha10 transgene restored nAChR function. However, in the alpha10 transgenic mice, no synaptic or ACh-evoked currents were observed in P16-18 IHCs, indicating developmental down-regulation of functional nAChRs after the onset of hearing, as normally observed in wild-type mice. The lack of functional ACh currents correlated with the lack of SK2 currents. These results indicate that multiple features of the efferent postsynaptic complex to IHCs, in additionto the nAChR subunits, are down-regulated in synchrony after the onset of hearing, leading to lack of responses to ACh. | ||||
| 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. | ||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.