Fisher Janet L
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Blg 1 Rm D23, Columbia, SC 29209, USA.
Neuropharmacology. 2004 Apr;46(5):629-37. doi: 10.1016/j.neuropharm.2003.11.015.
A genetic component is associated with the development of many forms of epilepsy. Recently, mutations in the GABAA receptor have been linked to several inherited epilepsies. One of these mutations is a non-conservative change of alanine to aspartate in the third transmembrane domain of the alpha1 subunit. To determine the functional consequences of this alteration, mutated alpha subunits were transiently transfected along with wild-type beta3 and gamma2L subunits into HEK-293T cells. The mutated alpha1(A294D) subunit reduced GABA sensitivity of the receptor, increased the deactivation rate and slowed desensitization. The mutation caused a reduction in channel open time but no change in single channel conductance. Studies with additional mutants, altering the charge and/or size of the side-chain, indicated that both size and hydrophobicity of the residue at this location influence channel gating. The effects on GABA sensitivity, deactivation rate and channel open time are consistent with a reduced efficacy of channel gating, and would be expected to decrease GABAergic neurotransmission. The alpha1 subtype is the most widely expressed of the alpha subunits, with expression increasing throughout development. Therefore, production of the mutated subunit could cause global hyperexcitability throughout the brain, leading to generalized seizures with juvenile onset.
遗传因素与多种形式癫痫的发生发展相关。最近，γ-氨基丁酸A型（GABAA）受体的突变已与几种遗传性癫痫相关联。其中一种突变是α1亚基第三个跨膜结构域中的丙氨酸非保守性转变为天冬氨酸。为了确定这种改变的功能后果，将突变的α亚基与野生型β3和γ2L亚基一起瞬时转染到HEK-293T细胞中。突变的α1（A294D）亚基降低了受体对γ-氨基丁酸（GABA）的敏感性，提高了失活速率并减缓了脱敏过程。该突变导致通道开放时间缩短，但单通道电导没有变化。对其他突变体的研究，改变了侧链的电荷和/或大小，表明该位置残基的大小和疏水性均影响通道门控。对GABA敏感性、失活速率和通道开放时间的影响与通道门控效率降低一致，并且预计会减少GABA能神经传递。α1亚型是α亚基中表达最广泛的，其表达在整个发育过程中增加。因此，突变亚基的产生可能导致全脑整体兴奋性过高，导致青少年期发作的全身性癫痫。
