Altered GABA(A) receptor subunit expression and pharmacology in human Angelman syndrome cortex.
Altered GABA(A) receptor subunit expression and pharmacology in human Angelman syndrome cortex.
复制标题
改变人类天使综合征皮质中的 GABA(A) 受体亚基表达和药理学。
DOI：
10.1016/j.neulet.2010.08.001
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发表时间：
2010
影响因子：
2.5
通讯作者：
Jansen,LauraA
中科院分区：
文献类型：
--
作者：
Roden,WilliamH;Peugh,LindseyD;Jansen,LauraA
神经发育障碍Angelman综合征最常见的原因是母源性染色体15 q11-q13区域的缺失，该区域不仅包括致病的UBE 3A基因，还包括β3-α5-γ 3GABAA受体亚基基因簇。GABA能功能障碍已被假设为有助于癫痫的发生以及这种情况下的认知和行为障碍。在本研究中，分析GABAA受体亚单位的表达和药理学进行了大脑皮层从四个受试者与Angelman综合征，并从控制组织进行比较。分离冷冻死后新皮质组织的膜部分并进行定量Western印迹分析。Angelman综合征患者大脑皮质β3/β 2、α5/α 1亚基蛋白表达比值较正常对照组明显降低。将另外的膜组分注射到爪蟾卵母细胞中，导致脑膜囊泡及其相关受体并入卵母细胞细胞膜中。然后进行GABA A受体电流的双电极电压钳分析。Angelman综合征皮质GABA A受体药理学研究显示，α1-选择性苯二氮卓类位点激动剂唑吡坦和巴比妥类药物苯巴比妥可增加电流增强，而锌对电流抑制的敏感性降低。GABAA受体亲和力和神经类固醇的调节没有变化。Angelman综合征中GABA A受体亚单位表达和药理学的这种变化与突触外受损一致，但与突触皮质GABA能抑制增强一致，这可能导致该疾病的癫痫、行为和认知表型。
The neurodevelopmental disorder Angelman syndrome is most frequently caused by deletion of the maternally derived chromosome 15q11-q13 region, which includes not only the causative UBE3A gene, but also the β3-α5-γ3GABAAreceptor subunit gene cluster. GABAergic dysfunction has been hypothesized to contribute to the occurrence of epilepsy and cognitive and behavioral impairments in this condition. In the present study, analysis of GABAAreceptor subunit expression and pharmacology was performed in cerebral cortex from four subjects with Angelman syndrome and compared to that from control tissue. The membrane fraction of frozen postmortem neocortical tissue was isolated and subjected to quantitative Western blot analysis. The ratios of β3/β2and α5/α1subunit protein expression in Angelman syndrome cortex were significantly decreased when compared with controls. An additional membrane fraction was injected into Xenopus oocytes, resulting in incorporation of the brain membrane vesicles with their associated receptors into the oocyte cellular membrane. Two-electrode voltage-clamp analysis of GABAAreceptor currents was then performed. Studies of GABAAreceptor pharmacology in Angelman syndrome cortex revealed increased current enhancement by the α1-selective benzodiazepine-site agonist zolpidem and by the barbiturate phenobarbital, while sensitivity to current inhibition by zinc was decreased. GABAAreceptor affinity and modulation by neurosteroids were unchanged. This shift in GABAAreceptor subunit expression and pharmacology in Angelman syndrome is consistent with impaired extrasynaptic but intact to augmented synaptic cortical GABAergic inhibition, which could contribute to the epileptic, behavioral, and cognitive phenotypes of the disorder.