Li Boxing, Tadross Michael R, Tsien Richard W
Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA.
Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Science. 2016 Feb 19;351(6275):863-7. doi: 10.1126/science.aad3647.
Voltage-gated CaV1.2 channels (L-type calcium channel α1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VΔC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VΔC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VΔC by 10 to 20 seconds. CaV1.2 VΔC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VΔC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VΔC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.
电压门控CaV1.2通道（L型钙通道α1C亚基）是转录依赖性神经可塑性的关键介质。到目前为止，这些通道是通过钙离子（Ca(2+)）内流、电压依赖性构象变化（VΔC）还是两者结合来传递信号仍不明确。我们将CaV1.2与配体门控的Ca(2+)通透通道融合，从而能够独立控制局部Ca(2+)和VΔC信号。这揭示了一个意想不到的双重要求：Ca(2+)必须首先动员与肌动蛋白结合的Ca(2+)/钙调蛋白依赖性蛋白激酶II，使其释放出来以便随后由VΔC介导积累。单独任何一个信号都不足以激活转录。信号顺序至关重要：当Ca(2+)先于VΔC 10到20秒时效率达到峰值。CaV1.2 VΔC协同增强N-甲基-D-天冬氨酸受体的信号传导。此外，VΔC失调与蒂莫西综合征中的自闭症症状相关。因此，非离子型VΔC信号传导对于CaV1.2在突触和神经精神过程中的功能至关重要。
