Pokorska Anna, Vanhoutte Peter, Arnold Fiona J L, Silvagno Francesca, Hardingham Giles E, Bading Hilmar
MRC Laboratory of Molecular Biology, Division of Neurobiology, Hills Road, Cambridge, UK.
J Neurochem. 2003 Feb;84(3):447-52. doi: 10.1046/j.1471-4159.2003.01504.x.
Nuclear calcium signals associated with electrical activation of neurons can control the activity of the transcription factor cAMP-response element binding protein (CREB). Yet, cAMP is thought to be the key messenger that links synaptic activity to the regulation of CREB-mediated transcription. It is generally assumed that synaptic activity increases the intracellular levels of cAMP; this causes activation of the cAMP-dependent protein kinase (PKA) that regulates CREB-mediated transcription either directly or through controlling nuclear signalling of the MAP kinases/extracellular signal-regulated kinases (ERK1/2) pathway. Here we show that, in hippocampal neurons, synaptic activity failed to increase global levels of cAMP that would be required for the cAMP-PKA system to induce nuclear events. Even near-continuous bursting of action potentials, giving rise to large nuclear calcium signals and robust CREB-dependent transcription, left global intracellular levels of cAMP unchanged. These results suggest that the cAMP-PKA system does not function as the transducer of synaptic signals to the nucleus. They indicate that the known inhibitory effects of blockers of PKA on gene expression and long-lasting plasticity triggered by calcium entry reflect a gating function of basal activity of PKA that renders neurons permissive for nuclear calcium-regulated, CREB/CBP-dependent gene expression.
与神经元电活动相关的核钙信号可控制转录因子环磷酸腺苷反应元件结合蛋白（CREB）的活性。然而，人们认为环磷酸腺苷（cAMP）是将突触活动与CREB介导的转录调控联系起来的关键信使。一般认为突触活动会增加细胞内cAMP的水平；这会导致环磷酸腺苷依赖性蛋白激酶（PKA）的激活，PKA可直接或通过控制丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK1/2）途径的核信号来调节CREB介导的转录。在此我们表明，在海马神经元中，突触活动未能增加cAMP-PKA系统诱导核事件所需的整体cAMP水平。即使是近乎连续的动作电位爆发，产生大量的核钙信号和强大的CREB依赖性转录，细胞内整体cAMP水平仍保持不变。这些结果表明，cAMP-PKA系统并非作为突触信号向细胞核的转导器发挥作用。它们表明，PKA阻滞剂对钙内流引发的基因表达和长期可塑性的已知抑制作用反映了PKA基础活性的一种门控功能，这种功能使神经元能够进行核钙调节的、依赖CREB/CBP的基因表达。
