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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Divergent sodium channel defects in familial hemiplegic migraine
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Divergent sodium channel defects in familial hemiplegic migraine

机译：家族性偏瘫偏头痛的钠通道缺陷

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摘要

Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na_v1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coex-pressed in tsA201 cells with the human β_1 and β_2 accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na_v1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na_v1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.
机译：家族性偏瘫3型偏头痛（FHM3）是一种严重的常染色体显性偏头痛，由SCN1A编码的电压门控钠通道Na_v1.1的突变引起。我们确定了与FHM3（L263V，Q1489K和L1649Q）关联的三个突变的功能后果，以鉴定这种遗传性偏头痛疾病的分子缺陷。当与人β_1和β_2辅助亚基在tsA201细胞中共表达时，只有L263V和Q1489K产生可量化的钠电流。第三个突变体L1649Q由于细胞表面表达明显降低而无法产生可测量的全细胞电流。与WT-Na_v1.1相比，Q1489K表现出增加的持续电流，但进入慢速灭活的能力增强，并且从快速和慢速灭活的恢复延迟，从而导致主要的功能丧失表型进一步表现为更大的通道损失重复刺激期间的可用性。相比之下，L263V具有功能增益功能，包括延迟进入快速灭活以及加速从快速灭活中的恢复。快速和慢速灭活的稳态电压依赖性中的去极化变化；持续电流增加；并延迟进入缓慢的失活状态。值得注意的是，表现出部分或完全功能丧失的两个突变（Q1489K和L1649Q）与典型的FHM相关，而功能获得性突变L263V发生在同时具有FHM和高发病率的家庭中。我们从这些数据推断出，Na_v1.1缺陷的复杂频谱会导致FHM3。我们的研究结果还强调了偏头痛和癫痫之间的复杂关系，并提供了进一步的证据表明这两种疾病可能具有共同的分子机制。

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