Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor
Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor
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DOI：
10.1073/pnas.96.10.5746
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发表时间：
1999-05-11
影响因子：
11.1
通讯作者：
Beaudet, AL
中科院分区：
文献类型：
--
作者：
Xu, W;Gelber, S;Beaudet, AL
神经元烟碱乙酰胆碱受体的α 3亚基在自主神经节和大脑的某些部位广泛表达，α 3亚基可以与其他α亚基以及β 2和β 4亚基形成异多聚离子通道，但其在体内的功能尚不清楚。我们通过删除第5外显子制备了α 3基因的零突变，发现纯合子（-/-）小鼠在Northern blotting上缺乏可检测的mRNA， -/-小鼠存活至出生，但在断奶前后生长受损，死亡率增加，-/-小鼠有严重的膀胱增大，小便滴漏，膀胱感染，尿路结石，瞳孔广泛扩大，不能对光线做出反应。对-/-小鼠的详细组织学研究显示，除了膀胱炎症突出外，大脑或外周组织没有明显异常。膀胱和肠道中存在神经节细胞和轴突。-/-小鼠的膀胱条对0.1 mPrl尼古丁没有反应收缩，但对电场刺激或氨基甲酰胆碱有反应收缩。野生型小鼠具有不同电导和动力学特性的5种生理上可区分的烟碱乙酰胆碱受体亚型-/-小鼠颈上神经节神经元中乙酰胆碱激活的单通道电流数量严重减少，在-/-小鼠中均减少。在α 3缺失小鼠中的发现表明，该亚基是介导自主神经系统正常功能的尼古丁受体的重要组成部分。-/-小鼠的表型可能与罕见的人类遗传疾病巨囊-微结肠-肠蠕动迟缓综合征相似。
The alpha 3 subunit of the neuronal nicotinic acetylcholine receptor is widely expressed in autonomic ganglia and in some parts of the brain, The alpha 3 subunit can form heteromultimeric ion channels with other alpha subunits and with beta 2 and beta 4 subunits, but its function in vivo is poorly understood. We prepared a null mutation for the alpha 3 gene by deletion of exon 5 and found that homozygous (-/-) mice lacked detectable mRNA on Northern blotting, The -/- mice survive to birth but have impaired growth and increased mortality before and after weaning, The -/- mice have extreme bladder enlargement, dribbling urination, bladder infection, urinary stones, and widely dilated ocular pupils that do not contract in response to light, Detailed histological studies of -/- mice revealed no significant abnormalities in brain or peripheral tissues except urinary bladder, where inflammation was prominent. Ganglion cells and axons were present in bladder and bowel, Bladder strips from -/- mice failed to contract in response to 0.1 mPrl nicotine, but did contract in response to electrical field stimulation or carbamoylcholine, The number of acetylcholine-activated single-channel currents was severely reduced in the neurons of superior cervical ganglia in -/- mice with five physiologically distinguishable nicotinic acetylcholine receptor subtypes with different conductance and kinetic properties in wild-type mice, all of which were reduced in -/- mice. The findings in the alpha 3-null mice suggest that this subunit is an essential component of the nicotinic receptors mediating normal function of the autonomic nervous system. The phenotype in -/- mice may be similar to the rare human genetic disorder of megacystis-microcolon-intestinal hypoperistalsis syndrome.