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首页> 外文期刊>The Journal of biological chemistry >GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors
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GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

机译：GABAA受体α1亚基突变A322D与常染色体占优势幼虫肌阵挛性癫痫减少表达并改变了野生型GABAA受体的组成

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A GABAA receptor (GABAAR) α1 subunit mutation, A322D (AD), causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJME). Previous studies demonstrated that the mutation caused α1(AD) subunit misfolding and rapid degradation, reducing its total and surface expression substantially. Here, we determined the effects of the residual α1(AD) subunit expression on wild type GABAAR expression to determine whether the AD mutation conferred a dominant negative effect. We found that although the α1(AD) subunit did not substitute for wild type α1 subunits on the cell surface, it reduced the surface expression of α1β2γ2 and α3β2γ2 receptors by associating with the wild type subunits within the endoplasmic reticulum and preventing them from trafficking to the cell surface. The α1(AD) subunit reduced surface expression of α3β2γ2 receptors by a greater amount than α1β2γ2 receptors, thus altering cell surface GABAAR composition. When transfected into cultured cortical neurons, the α1(AD) subunit altered the time course of miniature inhibitory postsynaptic current kinetics and reduced miniature inhibitory postsynaptic current amplitudes. These findings demonstrated that, in addition to causing a heterozygous loss of function of α1(AD) subunits, this epilepsy mutation also elicited a modest dominant negative effect that likely shapes the epilepsy phenotype.
机译：GABAA受体（GABAAR）α1亚基突变，A322D（AD），导致幼年肌阵挛性癫痫（ADDME）的常染色体显性形式。以前的研究表明，突变引起α1（Ad）亚单位误折叠和快速降解，基本上降低了其总和表面表达。这里，我们确定了残留α1（Ad）亚基表达对野生型GABAAR表达的影响，以确定广告突变是否赋予显性负效应。我们发现虽然α1（Ad）亚基未替代细胞表面上的野生型α1亚基，但它通过与内质网内的野生型亚基相关并防止它们贩运群体的α1β2γ2和α3β2γ2受体的表面表达降低细胞表面。 α1（Ad）亚单位减少α3β2γ2受体的表面表达比α1β2γ2受体更大的量，从而改变细胞表面gabaAR组合物。当转染到培养的皮质神经元时，α1（Ad）亚基改变了微型抑制突触突触突触电流动力学的时间过程，并减少了微型抑制突触突触突触电流幅度。这些发现证明，除了引起α1（AD）亚基功能的杂合丧失，这种癫痫突变还引发了适度的显性负面影响，这可能造型癫痫表型。

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