A polymorphism in the mouse neuronal α4 nicotinic receptor subunit results in an alteration in receptor function
A polymorphism in the mouse neuronal α4 nicotinic receptor subunit results in an alteration in receptor function
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DOI：
10.1124/mol.62.2.334
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发表时间：
2002-08-01
影响因子：
3.6
通讯作者：
Stitzel, JA
中科院分区：
文献类型：
--
作者：
Dobelis, P;Marks, MJ;Stitzel, JA
尼古丁刺激的 Rb-86(+) 流出和 [H-3] 金雀花氨酸结合似乎都能测量由 α4 和 β2 亚基组成的烟碱乙酰胆碱受体，并在从 14 只近交小鼠品系获得的 8 个脑区中进行了评估。还评估了烟碱受体 α4 亚基基因 (Chrna4) 中的单核苷酸多态性 (SNP) 对小鼠烟碱受体结合和功能的潜在作用。该 SNP 导致新生 α4 亚基多肽的氨基酸位置 529 处丙氨酸变为苏氨酸。尼古丁刺激的 Rb-86(+) 流出和 [H-3] 金雀花氨酸结合被发现在不同大脑区域和小鼠品系之间存在差异。每个菌株内尼古丁刺激的 Rb-86(+) 流出量的变异性与 [H-3] 金雀花碱结合位点的数量呈正相关 (r > 0.9)。然而，[H-3] 金雀花碱结合位点的数量与尼古丁刺激的 Rb-86(+) 小鼠品系外流无关。相比之下，Chrna4 多态性与小鼠品系的受体功能相关：在携带 Chrna4 的 Ala-529 变体的小鼠品系中研究的 8 个脑区中，有 7 个区域的 Rb-86(+) 流出量更大。 Chrna4 SNP 似乎不影响小鼠品系中 [H-3] 金雀花氨酸结合位点的数量。这些数据表明，近交系小鼠品系表现出受体功能差异，这种差异不能归因于受体表达的变化，但至少部分可以通过α4亚基的错义多态性来解释。
Nicotine-stimulated Rb-86(+) efflux and [H-3] cytisine binding, both of which seem to measure the nicotinic acetylcholine receptor, composed of alpha4 and beta2 subunits, were assessed in eight brain regions obtained from 14 inbred mouse strains. The potential role of a single nucleotide polymorphism (SNP) in the nicotinic receptor alpha4 subunit gene (Chrna4) on nicotinic receptor binding and function in mice was also evaluated. This SNP leads to an alanine-to-threonine variation at amino acid position 529 of the nascent alpha4 subunit polypeptide. Both nicotine-stimulated Rb-86(+) efflux and [H-3] cytisine binding were found to vary across brain regions and among mouse strains. Variability in nicotine-stimulated Rb-86(+) efflux was positively correlated (r > 0.9) within each strain with the number of [H-3] cytisine binding sites. However, the number of [H-3] cytisine binding sites was not correlated with nicotine-stimulated Rb-86(+) efflux across mouse strains. In contrast, the Chrna4 polymorphism was associated with receptor function across mouse strains: Rb-86(+) efflux was greater in seven of the eight brain regions studied in those mouse strains that carry the Ala-529 variant of Chrna4. The Chrna4 SNP did not seem to influence the number of [H-3] cytisine binding sites across mouse strains. These data indicate that inbred mouse strains exhibit differences in receptor function that cannot be attributed to variation in receptor expression but may be explained, at least in part, by the missense polymorphism in the alpha4 subunit.