Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147.
Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15794-9. doi: 10.1073/pnas.1313898110. Epub 2013 Sep 9.
Local Ca(2+) signals through voltage-gated Ca(2+) channels (CaVs) drive synaptic transmission, neural plasticity, and cardiac contraction. Despite the importance of these events, the fundamental relationship between flux through a single CaV channel and the Ca(2+) signaling concentration within nanometers of its pore has resisted empirical determination, owing to limitations in the spatial resolution and specificity of fluorescence-based Ca(2+) measurements. Here, we exploited Ca(2+)-dependent inactivation of CaV channels as a nanometer-range Ca(2+) indicator specific to active channels. We observed an unexpected and dramatic boost in nanodomain Ca(2+) amplitude, ten-fold higher than predicted on theoretical grounds. Our results uncover a striking feature of CaV nanodomains, as diffusion-restricted environments that amplify small Ca(2+) fluxes into enormous local Ca(2+) concentrations. This Ca(2+) tuning by the physical composition of the nanodomain may represent an energy-efficient means of local amplification that maximizes information signaling capacity, while minimizing global Ca(2+) load.
局部钙离子信号通过电压门控钙离子通道（CaVs）驱动突触传递、神经可塑性和心脏收缩。尽管这些事件非常重要，但由于荧光钙离子测量的空间分辨率和特异性的限制，单个 CaV 通道的通量与其孔内钙离子信号浓度之间的基本关系仍然难以确定。在这里，我们利用 CaV 通道的钙离子依赖性失活作为一种纳米级钙离子指示剂，专门针对活性通道。我们观察到纳米域钙离子幅度的意外和显著增强，比理论预测高出十倍。我们的结果揭示了 CaV 纳米域的一个显著特征，即扩散受限的环境将小的钙离子通量放大为巨大的局部钙离子浓度。这种由纳米域的物理组成引起的钙离子调谐可能代表了一种能量有效的局部放大方式，最大限度地提高了信息信号传递能力，同时最小化了全局钙离子负荷。
