Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse
Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse
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DOI：
10.1038/ng991
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发表时间：
2002-10-01
期刊：
影响因子：
30.8
通讯作者：
Bucan, M
中科院分区：
文献类型：
--
作者：
Kapfhamer, D;Valladares, O;Bucan, M
Rab3a 是大脑中最丰富的 Rab（ras 相关结合）蛋白，在突触小泡运输中具有调节作用 (1)。 Rab3a 发生靶向功能丧失突变的小鼠存在 Ca2+ 依赖性突触传递缺陷：响应动作电位而释放的囊泡数量比野生型小鼠多，导致更大的突触抑制 (2,3) 和 CA3 苔藓纤维长期增强 (4)。这些变化对行为的影响尚不清楚。在筛选具有异常休息活动和睡眠模式的小鼠突变体时，我们发现了一种称为早鸟的半显性突变，它缩短了运动活动的昼夜节律周期。 Rab3a 的序列分析发现，早期突变体中该蛋白的 GTP 结合域内的保守氨基酸 (Asp77Gly) 存在点突变，导致 Rab3a 蛋白水平显着降低。对早鸟小鼠和 Rab3a 无效等位基因的表型评估揭示了昼夜节律和睡眠稳态的异常，这提供了 Rab3a 介导的突触传递参与这些行为的证据。
Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking(1). Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca2+-dependent synaptic transmission: the number of vesicles released in response to an action potential is greater than in wildtype mice, resulting in greater synaptic depression(2,3) and the abolishment of CA3 mossy-fiber long term potentiation(4). The effect of these changes on behavior is unknown. In a screen for mouse mutants with abnormal rest-activity and sleep patterns, we identified a semidominant mutation, called earlybird, that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (Asp77Gly) within the GTP-binding domain of this protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors.