de Juan-Sanz Jaime, Holt Graham T, Schreiter Eric R, de Juan Fernando, Kim Douglas S, Ryan Timothy A
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Neuron. 2017 Feb 22;93(4):867-881.e6. doi: 10.1016/j.neuron.2017.01.010. Epub 2017 Feb 2.
Although the endoplasmic reticulum (ER) extends throughout axons and axonal ER dysfunction is implicated in numerous neurological diseases, its role at nerve terminals is poorly understood. We developed novel genetically encoded ER-targeted low-affinity Ca indicators optimized for examining axonal ER Ca. Our experiments revealed that presynaptic function is tightly controlled by ER Ca content. We found that neuronal activity drives net Ca uptake into presynaptic ER although this activity does not contribute significantly to shaping cytosolic Ca except during prolonged repetitive firing. In contrast, we found that axonal ER acts as an actuator of plasma membrane (PM) function: [Ca] controls STIM1 activation in presynaptic terminals, which results in the local modulation of presynaptic function, impacting activity-driven Ca entry and release probability. These experiments reveal a critical role of presynaptic ER in the control of neurotransmitter release and will help frame future investigations into the molecular basis of ER-driven neuronal disease states.
尽管内质网（ER）贯穿轴突，且轴突内质网功能障碍与多种神经系统疾病有关，但其在神经末梢的作用却知之甚少。我们开发了新型的基因编码内质网靶向低亲和力钙指示剂，用于检测轴突内质网钙。我们的实验表明，突触前功能受内质网钙含量的严格控制。我们发现，神经元活动驱动净钙摄取到突触前内质网中，尽管这种活动除了在长时间重复放电期间外，对塑造胞质钙的作用不大。相反，我们发现轴突内质网作为质膜（PM）功能的一个促动器：内质网钙浓度控制突触前末梢中基质相互作用分子1（STIM1）的激活，这导致突触前功能的局部调节，影响活动驱动的钙内流和释放概率。这些实验揭示了突触前内质网在控制神经递质释放中的关键作用，并将有助于推动未来对内质网驱动的神经元疾病状态分子基础的研究。
