Transcriptional regulation of neuronal genes and its effect on neural functions: Cumulative mRNA expression of PACAP and BDNF genes controlled by calcium and cAMP signals in neurons
Transcriptional regulation of neuronal genes and its effect on neural functions: Cumulative mRNA expression of PACAP and BDNF genes controlled by calcium and cAMP signals in neurons
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DOI：
10.1254/jphs.fmj05001x4
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Tsuda, M
中科院分区：
文献类型：
--
作者：
Fukuchi, M;Tabuchi, A;Tsuda, M
虽然人们普遍认为神经元中的钙（Ca 2+）信号诱导活性依赖性基因转录，但仍然不清楚特定的mRNA部分如何响应于引起包括Ca 2+和cAMP信号在内的多种细胞内信号的突触传递而瞬时积累。脑源性神经营养因子（BDNF）和垂体腺苷酸环化酶激活多肽（PACAP）的启动子通常可以通过cAMP反应元件（CRE）激活，CRE结合蛋白（CREB）主要结合cAMP反应元件（CRE）。BDNF基因启动子I和III（分别为BDNF-PI和-PIII）的激活不仅由CREB而且由上游刺激因子介导，而PACAP基因启动子（PACAP-P）的激活仅由位于-200附近的一个CRE介导。PACAP-P通过CRE被Ca 2+和cAMP信号协同增强，而BDNF-PI在两种信号刺激下没有显示出这种协同激活。此外，我们发现Ca 2+内流进入神经元会延长PACAP和BDNF mRNA的半衰期，但Arc mRNA的半衰期不会延长，这表明神经元中特定mRNA种类的稳定性依赖于活动。因此，活性依赖性基因表达不仅在转录水平上而且在转录后水平上由Ca 2+和cAMP信号协调控制神经元中的累积mRNA表达。
Although it is widely accepted that an activity-dependent gene transcription is induced by the calcium (Ca2+) signals in neurons, it is still unclear how the particular mRNA moieties are transiently accumulated in response to synaptic transmission that evokes multiple intracellular signals including Ca2+ and cAMP ones. Promoters of the brain-derived neurotrophic factor (BDNF) and the pituitary adenylate cyclase-ativating polypeptide (PACAP) can commonly be activated through the cAMP-responsive element (CRE), to which the CRE-binding protein (CREB) predominantly bound. The activation of BDNF gene promoter I and Ill (BDNF-PI and -PIII, respectively) was mediated not only by the CREB but also by the upstream stimulatory factor, whereas that of PACAP gene promoter (PACAP-P) was mediated by only one CRE located at around -200. The PACAP-P was synergistically enhanced by Ca2+ and cAMP signals through the CRE, whereas the BDNF-PI did not show such a synergistic activation upon the stimulation with both signals. In addition, we found that the half-lives of PACAP and BDNF mRNA were prolonged by the Ca2+ influx into neurons but not that of Arc mRNA, indicating an activity-dependent stabilization of particular mRNA species in neurons. Thus, the activity-dependent gene expression is co-ordinately controlled by Ca2+ and cAMP signals not only at the transcriptional level but also at the post-transcriptional level for the cumulative mRNA expression in neurons.