An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2+)-dependent regulation.
An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2+)-dependent regulation.
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DOI：
10.1038/srep27235
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发表时间：
2016-06-03
影响因子：
4.6
通讯作者：
Yue DT
中科院分区：
文献类型：
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作者：
Limpitikul WB;Dick IE;Ben-Johny M;Yue DT
CaV1.3通道是一类主要的L钙通道，参与心脏和大脑的节律性。在大脑中，这些通道对激发-转录耦合、突触可塑性和神经元放电至关重要。此外，CaV1.3功能的中断与几种神经疾病有关。在这里，我们关注的是新生的错义突变A760G，它与自闭症谱系障碍(ASD)有关。为了探讨该突变在ASD发病机制中的作用，我们研究了A760G对CaV1.3通道门控和调节的影响。该突变的引入严重削弱了CaV1.3通道的钙依赖失活(CDI)，这是钙稳态所需的一个重要反馈系统。CDI的这种减少在两个主要的通道剪接变体中观察到，尽管程度不同。利用通道门控的变构模型，我们发现CDI减少的潜在机制可能是由于钙失活模式中通道开放的增强。值得注意的是，A760G突变也导致电压依赖失活(VDI)的相反增加，导致ASD潜在的多方面机制。当这些调节缺陷结合在一起时，似乎会增加细胞内的钙离子浓度，从而潜在地扰乱神经元的发育和突触的形成，最终导致ASD。
CaV1.3 channels are a major class of L-type Ca2+ channels which contribute to the rhythmicity of the heart and brain. In the brain, these channels are vital for excitation-transcription coupling, synaptic plasticity, and neuronal firing. Moreover, disruption of CaV1.3 function has been associated with several neurological disorders. Here, we focus on the de novo missense mutation A760G which has been linked to autism spectrum disorder (ASD). To explore the role of this mutation in ASD pathogenesis, we examined the effects of A760G on CaV1.3 channel gating and regulation. Introduction of the mutation severely diminished the Ca2+-dependent inactivation (CDI) of CaV1.3 channels, an important feedback system required for Ca2+ homeostasis. This reduction in CDI was observed in two major channel splice variants, though to different extents. Using an allosteric model of channel gating, we found that the underlying mechanism of CDI reduction is likely due to enhanced channel opening within the Ca2+-inactivated mode. Remarkably, the A760G mutation also caused an opposite increase in voltage-dependent inactivation (VDI), resulting in a multifaceted mechanism underlying ASD. When combined, these regulatory deficits appear to increase the intracellular Ca2+ concentration, thus potentially disrupting neuronal development and synapse formation, ultimately leading to ASD.