Genç Özgür, Dickman Dion K, Ma Wenpei, Tong Amy, Fetter Richard D, Davis Graeme W
Department of Biochemistry and Biophysics, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States.
Department of Biological Sciences, University of Southern California, Los Angeles, United States.
Elife. 2017 May 9;6:e22904. doi: 10.7554/eLife.22904.
Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission.
突触前稳态可塑性（PHP）在从线虫到人类的生物体中控制突触传递，并且据推测与人类疾病的病因相关。然而，PHP的潜在分子机制刚刚开始显现，其与疾病的直接关联仍不明确。在一项针对阻断PHP的突变进行的正向遗传学筛选中，我们鉴定出了MCTP（具有两个跨膜区域的多个C2结构域蛋白）。在此我们表明，MCTP定位于内质网（ER）的膜上，内质网在整个胞体、树突、轴突和突触前终末广泛分布。然后，我们证明MCTP在突触前钙内流的下游发挥作用，具有可分离的活性来稳定基线传递、短期释放动力学和PHP。值得注意的是，PHP特别需要MCTP三个C2结构域中每个结构域的钙配位残基。因此，我们提出MCTP作为一种新型的、定位于内质网的钙传感器以及用于神经传递稳态稳定的钙依赖性反馈来源。
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