A rare schizophrenia risk variant of CACNA1I disrupts Ca(V)3.3 channel activity.
A rare schizophrenia risk variant of CACNA1I disrupts Ca(V)3.3 channel activity.
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DOI：
10.1038/srep34233
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发表时间：
2016-10-19
影响因子：
4.6
通讯作者：
Pan JQ
中科院分区：
文献类型：
--
作者：
Andrade A;Hope J;Allen A;Yorgan V;Lipscombe D;Pan JQ
CACNA1I是精神分裂症的候选易感基因。它编码人类CaV3.3α1亚基形成孔的亚基，这是电压门控钙通道的一种亚型，对T型电流有贡献。最近，在精神分裂症患者中发现了hCaV3.3的两个新的错义变异，T797M和R1346H。在这里，我们发现R1346H，而不是T797M，与野生型相比，在人类细胞系中表达时与hCaV3.3蛋白水平降低，糖基化减少，以及hCaV3.3膜表面水平降低有关。与我们的生化分析一致，表达R1346H变体的细胞的全细胞hCaV3.3电流约为表达WT hCaV3.3的细胞的50%，并且R1346H和T797M都没有改变通道的生物物理特性。利用神经元模拟环境，我们发现将hCaV3.3电流密度降低22%或更多可以消除模型丘脑网状核(TRN)神经元的反弹爆发。我们的分析表明，chr22：39665939G >； A CACNA1I的单个拷贝能够干扰CaV3.3通道依赖的功能，包括TRN神经元的反弹爆发，这可能与精神分裂症的病理生理学有关。
CACNA1I is a candidate schizophrenia risk gene. It encodes the pore-forming human CaV3.3 α1 subunit, a subtype of voltage-gated calcium channel that contributes to T-type currents. Recently, two de novo missense variations, T797M and R1346H, of hCaV3.3 were identified in individuals with schizophrenia. Here we show that R1346H, but not T797M, is associated with lower hCaV3.3 protein levels, reduced glycosylation, and lower membrane surface levels of hCaV3.3 when expressed in human cell lines compared to wild-type. Consistent with our biochemical analyses, whole-cell hCaV3.3 currents in cells expressing the R1346H variant were ~50% of those in cells expressing WT hCaV3.3, and neither R1346H nor T797M altered channel biophysical properties. Employing the NEURON simulation environment, we found that reducing hCaV3.3 current densities by 22% or more eliminates rebound bursting in model thalamic reticular nucleus (TRN) neurons. Our analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt CaV3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.
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