GABAA receptor β isoform protein expression in human alcoholic brain:: interaction with genotype
GABAA receptor β isoform protein expression in human alcoholic brain:: interaction with genotype
复制标题
DOI：
10.1016/j.neuint.2006.04.008
复制
发表时间：
2006-11-01
影响因子：
4.2
通讯作者：
Dodd, Peter R.
中科院分区：
文献类型：
--
作者：
Buckley, S. Tracey;Foley, Philomena F.;Dodd, Peter R.
人类受试者的慢性酒精滥用导致诸如上级额叶皮层等区域的神经元损失。减少GABA传输可能介导这一点。通过蛋白质印迹法分析了在高加索受试者尸检时获得的易损（上级额叶皮质）和备用（初级运动皮质）皮质组织中GABA（A）受体β（1）、β（2）和β（3）亚型蛋白的表达，并评估了酒精中毒候选基因的基因型的影响。对照组和酗酒者在两个皮层区域的基因型未分化的β 2或03表达在整体亚型表达上存在显著的区域差异，但在总体组中没有显著的差异。有显着的，区域选择性，DRD 2B，SLC 1A 2和APOE基因型与P蛋白表达的相互作用时，酗酒者与对照组相比。在每种情况下，拥有酗酒相关等位基因都会通过两种不同的机制增加病理易感区域的β（2）：β（3）比率。DRD 2B-B2、B2组的SFC β 2：β 3比值比DRD 2B-B1、B1组高22%，比DRMB-B2、B2对照组高17%。SLC 1A 2A 603纯合子酗酒者的SFC β（2）：β（3）比值比携带至少一个603 G等位基因的酗酒者高25%，比SLC 1A 2A 603纯合子对照高75%。缺乏APOE β 3等位基因的酗酒者的SFC β 2：β 3比率比至少有一个β 3等位基因的酗酒者高73%，比没有β 3等位基因的对照组高70%。ADHI C基因型也可区分病例组和对照组，但作用不局限于局部。GABRB 2和GRIN 2B基因型与P亚基表达模式的显著区域差异相关，但这不受酒精中毒状态的影响。DRD 2A和SLC 6A 4基因型对上述指标无显著影响。一组有限的基因型可能会影响这组高消费酗酒者的亚基表达。(c)2006爱思唯尔有限公司保留所有权利。
Chronic alcohol misuse by human subjects leads to neuronal loss in regions such as the superior frontal cortex. Reduced GABA transmission may mediate this. The expression of GABA(A) receptor beta(1), beta(2) and beta(3) isoform proteins was analyzed by western blotting in vulnerable (superior frontal cortex) and spared (primary motor cortex) cortical tissue obtained at autopsy from Caucasian subjects, and the effect of genotypes of candidate genes for alcoholism assessed. There was a significant regional difference in global isoform expression, but no significant overall group difference in beta(2) or 03 expression between controls and alcoholics undifferentiated by genotype in either cortical region. There were significant, regionally selective, interactions of DRD2B, SLC1A2 and APOE genotypes with P protein expression when alcoholics were compared with controls. In each instance possession of the alcoholism-associated allele increased the beta(2):beta(3) ratio in the pathologically vulnerable region, by two distinct mechanisms. The SFC beta(2):beta(3) ratio in DRD2B-B2,B2 alcoholics was 22% higher than that in DRD2B-B1,B1 alcoholics, and 17% higher than that in DRMB-B2,B2 controls. The SFC beta(2):beta(3) ratio in SLC1A2A603 homozygote alcoholics was 25% higher than that in alcoholics with at least one 603G allele, and 75% higher than that in SLC1A2A603 homozygote controls. The SFC beta(2):beta(3) ratio in alcoholics lacking an APOE epsilon 3 allele was 73% higher than that in alcoholics with at least one epsilon 3 allele, and 70% higher than that in controls without an epsilon 3 allele. ADHI C genotype also differentiated cases and controls, but the effect was not localized. GABRB2 and GRIN2B genotypes were associated with significant regional differences in the pattern of P subunit expression, but this was not influenced by alcoholism status. DRD2A and SLC6A4 genotypes were without significant effect. A restricted set of genotypes may influence subunit expression in this group of high-consumption alcoholics. (c) 2006 Elsevier Ltd. All rights reserved.