Inhibition of L-Type Ca2+ Channels by TRPC1-STIM1 Complex Is Essential for the Protection of Dopaminergic Neurons
Inhibition of L-Type Ca2+ Channels by TRPC1-STIM1 Complex Is Essential for the Protection of Dopaminergic Neurons
复制标题
TRPC1-STIM1 复合物对 L 型 Ca(2 ) 通道的抑制对于保护多巴胺能神经元至关重要。
DOI：
10.1523/jneurosci.3010-16.2017
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发表时间：
2017-03-22
影响因子：
5.3
通讯作者：
Singh, Xbrij B.
中科院分区：
文献类型：
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作者：
Sun, Yuyang;Zhang, Haopeng;Singh, Xbrij B.
多巴胺能（DA）神经元的缺失导致帕金森病;然而，DA神经元的脆弱性的机制尚未完全理解。我们证明TRPC 1调节L型Ca 2+通道，该通道有助于黑质区域成年DA神经元的节律活动。通过STIM 1激活TRPC 1的存储耗尽抑制野生型DA神经元的节律活动的频率和幅度，但不抑制TRPC 1（-/-）小鼠。类似地，TRPC 1（-/-）黑质神经元显示增加的L型Ca 2+电流，减少刺激依赖性STIM 1-Ca（v）1.3相互作用，和减少DA神经元。TRPC 1激活后，L型Ca 2+电流和Ca（v）1.3通道的开放通道概率也降低，而STIM 1或TRPC 1沉默后观察到Ca（v）1.3电流增加。Ca（v）1.3-TRPC 1-STIM 1之间的相互作用在钙池耗尽后增加，TRPC 1或STIM 1的缺失导致DA细胞死亡，这通过抑制L型Ca 2+通道来防止。模拟帕金森病的神经毒素增加Ca（v）1.3功能，降低TRPC 1表达，抑制Tg介导的STIM 1-Ca（v）1.3相互作用，并诱导caspase活化。重要的是，TRPC 1表达的恢复不仅抑制Ca（v）1.3功能，而且增加细胞存活。总之，我们提供的证据表明，TRPC 1抑制Ca（v）1.3的活性，通过提供一个STIM 1为基础的支架，这是必不可少的DA神经元的生存。
Loss of dopaminergic (DA) neurons leads to Parkinson's disease; however, the mechanism(s) for the vulnerability of DA neurons is(are) not fully understood. We demonstrate that TRPC1 regulates the L-type Ca2+ channel that contributes to the rhythmic activity of adult DA neurons in the substantia nigra region. Store depletion that activates TRPC1, via STIM1, inhibits the frequency and amplitude of the rhythmic activity in DA neurons of wild-type, but not in TRPC1(-/-), mice. Similarly, TRPC1(-/-) substantia nigra neurons showed increased L-type Ca2+ currents, decreased stimulation-dependent STIM1-Ca(v)1.3 interaction, and decreased DA neurons. L-type Ca2+ currents and the open channel probability of Ca(v)1.3 channels were also reduced upon TRPC1 activation, whereas increased Ca(v)1.3 currents were observed upon STIM1 or TRPC1 silencing. Increased interaction between Ca(v)1.3-TRPC1-STIM1 was observed upon store depletion and the loss of either TRPC1 or STIM1 led to DA cell death, which was prevented by inhibiting L-type Ca2+ channels. Neurotoxins that mimic Parkinson's disease increased Ca(v)1.3 function, decreased TRPC1 expression, inhibited Tg-mediated STIM1-Ca(v)1.3 interaction, and induced caspase activation. Importantly, restoration of TRPC1 expression not only inhibited Ca(v)1.3 function but increased cell survival. Together, we provide evidence that TRPC1 suppresses Ca(v)1.3 activity by providing an STIM1-based scaffold, which is essential for DA neuron survival.