人酒精性脑病中GABA(A)受体β亚型蛋白表达：与基因型的相互作用

GABA(A) receptor beta isoform protein expression in human alcoholic brain: interaction with genotype.

作者信息

Buckley S Tracey, Foley Philomena F, Innes David J, Loh El-Wui, Shen Yi, Williams Susan M, Harper Clive G, Tannenberg Anthony E G, Dodd Peter R

机构信息

School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Australia.

出版信息

Neurochem Int. 2006 Nov;49(6):557-67. doi: 10.1016/j.neuint.2006.04.008.

DOI:10.1016/j.neuint.2006.04.008

PMID:16766085

Abstract

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 beta(3)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 beta 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 DRD2B-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 epsilon3 allele was 73% higher than that in alcoholics with at least one epsilon3 allele, and 70% higher than that in controls without an epsilon3 allele. ADH1C 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 beta 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.

摘要

人类长期滥用酒精会导致前额叶上等区域的神经元丧失。GABA传递减少可能介导了这一过程。采用蛋白质免疫印迹法分析了从白人受试者尸检中获取的易损（前额叶上皮质）和未受损（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效应。整体亚型表达存在显著的区域差异，但在两个皮质区域中，按基因型未区分的对照组和酒精中毒者之间，β(2)或β(3)表达在总体上没有显著的组间差异。当将酒精中毒者与对照组进行比较时，DRD2B、SLC1A2和APOE基因型与β蛋白表达存在显著的、区域选择性的相互作用。在每种情况下，与酒精中毒相关等位基因的存在通过两种不同机制增加了病理易损区域的β(2):β(3)比率。DRD2B - B2,B2酒精中毒者的前额叶上皮质β(2):β(3)比率比DRD2B - B1,B1酒精中毒者高22%，比DRD2B - B2,B2对照组高17%。SLC1A2 A603纯合子酒精中毒者的前额叶上皮质β(2):β(3)比率比至少有一个603G等位基因的酒精中毒者高25%，比SLC1A2 A603纯合子对照组高75%。缺乏APOE ε3等位基因的酒精中毒者的前额叶上皮质β(2):β(3)比率比至少有一个ε3等位基因的酒精中毒者高73%，比没有ε3等位基因的对照组高70%。ADH1C基因型也能区分病例和对照，但效应并不局限于特定区域。GABRB2和GRIN2B基因型与β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。DRD2A和SLC6A4基因型没有显著影响。一组有限的基因型可能会影响这组高饮酒量酒精中毒者的亚基表达。