Lalonde Jasmin, Saia Gregory, Gill Grace
Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Cell, Molecular & Developmental Biology Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
Sci Signal. 2014 Jun 3;7(328):ra51. doi: 10.1126/scisignal.2005242.
Calcium (Ca(2+)) signaling activated in response to membrane depolarization regulates neuronal maturation, connectivity, and plasticity. Store-operated Ca(2+) entry (SOCE) occurs in response to depletion of Ca(2+) from endoplasmic reticulum (ER), mediates refilling of this Ca(2+) store, and supports Ca(2+) signaling in nonexcitable cells. We report that maximal activation of SOCE occurred in cerebellar granule neurons cultured under resting conditions and that this Ca(2+) influx promoted the degradation of transcription factor Sp4, a regulator of neuronal morphogenesis and function. Lowering the concentration of extracellular potassium, a condition that reduces neuronal excitability, stimulated depletion of intracellular Ca(2+) stores, resulted in the relocalization of the ER Ca(2+) sensor STIM1 into punctate clusters consistent with multimerization and accumulation at junctions between the ER and plasma membrane, and induced a Ca(2+) influx with characteristics of SOCE. Compounds that block SOCE prevented the ubiquitylation and degradation of Sp4 in neurons exposed to a low concentration of extracellular potassium. Knockdown of STIM1 blocked degradation of Sp4, whereas expression of constitutively active STIM1 decreased Sp4 abundance under depolarizing conditions. Our findings indicated that, in neurons, SOCE is induced by hyperpolarization, and suggested that this Ca(2+) influx pathway is a distinct mechanism for regulating neuronal gene expression.
响应膜去极化而激活的钙（Ca(2+)）信号传导调节神经元的成熟、连接性和可塑性。钙库操纵性钙内流（SOCE）发生在内质网（ER）钙（Ca(2+)）耗竭时，介导该钙库的再填充，并支持非兴奋性细胞中的钙（Ca(2+)）信号传导。我们报告称，SOCE的最大激活发生在静息条件下培养的小脑颗粒神经元中，并且这种钙（Ca(2+)）内流促进了转录因子Sp4的降解，Sp4是神经元形态发生和功能的调节因子。降低细胞外钾离子浓度（一种降低神经元兴奋性的条件）会刺激细胞内钙（Ca(2+)）库的耗竭，导致内质网钙（Ca(2+)）传感器STIM1重新定位到点状簇中，这与内质网和质膜交界处的多聚化和积累一致，并诱导具有SOCE特征的钙（Ca(2+)）内流。阻断SOCE的化合物可防止暴露于低浓度细胞外钾离子的神经元中Sp4的泛素化和降解。敲低STIM1可阻断Sp4的降解，而组成型活性STIM1的表达在去极化条件下会降低Sp4的丰度。我们的研究结果表明，在神经元中，SOCE是由超极化诱导的，并表明这种钙（Ca(2+)）内流途径是调节神经元基因表达的一种独特机制。
