Nicotinic α5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers
Nicotinic α5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers
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DOI：
10.1111/j.1471-4159.2007.04700.x
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发表时间：
2007-10-01
影响因子：
4.7
通讯作者：
Whiteaker, Paul
中科院分区：
文献类型：
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作者：
Brown, Robert W. B.;Collins, Allan C.;Whiteaker, Paul
神经元型烟碱型乙酰胆碱受体α5亚单位在中枢神经系统中广泛表达。阿尔法5基因多态与小鼠品系之间的行为差异有关，阿尔法5零突变可导致小鼠对尼古丁的急性反应发生深刻变化。在这项研究中，我们研究了α5*烟碱型乙酰胆碱受体在小鼠脑内的分布和流行情况，并量化了α5零突变对突触前烟碱型乙酰胆碱受体功能(使用突触体86Rb(+)外流测量)和总的[I-125]表面胆碱结合位点表达的影响。在所研究的15个区域中有9个区域发现α5烟碱型乙酰胆碱受体的表达，尽管在任何区域中都有20%的烟碱型乙酰胆碱受体种群包含(α5)。(α5亚单位基因缺失导致局部功能丧失(丘脑、纹状体)，其本身仅限于DHPE敏感受体种群。受体表达未见变化。因此，每单位受体的功能改变必然会导致功能的改变。高激动剂激活亲和力位点的选择性耗尽导致整体烟碱功能降低，并增加整体激动剂激活亲和力。总之，这些结果描述了烟碱型乙酰胆碱受体a5亚单位缺失突变体对尼古丁的行为反应改变背后的受体水平的变化。
Neuronal nicotinic acetylcholine receptor subunit alpha 5 mRNA is widely expressed in the CNS. An alpha 5 gene polymorphism has been implicated in behavioral differences between mouse strains, and alpha 5-null mutation induces profound changes in mouse acute responses to nicotine. In this study, we have examined the distribution and prevalence of alpha 5* nicotinic acetylcholine receptor in mouse brain, and quantified the effects of alpha 5-null mutation on pre-synaptic nicotinic acetylcholine receptor function (measured using synaptosomal 86Rb(+) efflux) and overall [I-125]epibatidine binding site expression. alpha 5* nicotinic acetylcholine receptor expression was found in nine of fifteen regions examined, although alpha 5* < 20% of the total nicotinic acetylcholine receptor population in any region contained (alpha 5. Deletion of the (alpha 5 subunit gene resulted in localized loss of function (thalamus, striatum), which was itself confined to the DHPE-sensitive receptor population. No changes in receptor expression were seen. Consequently, functional changes must occur as a result of altered function per unit of receptor. The selective depletion of high agonist activation affinity sites results in overall nicotinic function being reduced, and increases the overall agonist activation affinity. Together, these results describe the receptor-level changes underlying altered behavioral responses to nicotine in nicotinic acetylcholine receptor a5 subunit-null mutants.