Regulation of cAMP-specific phosphodiesterases type 4B and 4D (PDE4) splice variants by cAMP signaling in primary cortical neurons
Regulation of cAMP-specific phosphodiesterases type 4B and 4D (PDE4) splice variants by cAMP signaling in primary cortical neurons
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DOI：
10.1046/j.1471-4159.2002.00878.x
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发表时间：
2002-05-01
影响因子：
4.7
通讯作者：
Duman, RS
中科院分区：
文献类型：
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作者：
D'Sa, C;Tolbert, LM;Duman, RS
本研究检测了cAMP信号对皮质神经元中所有已知磷酸二酯酶（PDE）型PDE4A、PDE4B和PDE4D剪接变体的调控。二丁基camp （db-cAMP）诱导了两种已知的剪接变体PDE4B2和PDE4D1/PDE4D2。虽然剪接变体PDE4A1、PDE4A5/PDE4A10、PDE4B3、PDE4B1、PDE4D3和PDE4D4在皮质神经元中存在，但它们的mRNA不受db-cAMP的转录水平调控。为了评估PDE4B2和PDE4D1/D2 mRNA表达的增加，我们对含有这些基因的启动子进行了表征。两个启动子的转录都受到db-cAMP的刺激。由于慢性抗抑郁治疗增加了PDE4B而不是PDE4D mRNA的表达，因此我们重点研究了cAMP和CREB对PDE4B2启动子的调节。CREB的显性阴性突变体抑制PDE4B2启动子活性，CREB的组成型活性形式强烈地刺激PDE4B2启动子活性。这些数据表明，在皮质神经元中，一个短的PDE4B2内含子启动子受CREB调控，赋予cAMP响应性，并指导PDE4B2 mRNA和蛋白的表达。
This study examined the regulation of all known phosphodiesterase (PDE) type PDE4A, PDE4B and PDE4D splice variants in cortical neurons by cAMP signaling. Treatment with dibutyryl-cAMP (db-cAMP) caused the induction of two of the known splice variants, PDE4B2 and PDE4D1/PDE4D2. Although the splice variants PDE4A1, PDE4A5/PDE4A10, PDE4B3, PDE4B1, PDE4D3 and PDE4D4 were present in cortical neurons, their mRNA was not regulated at the transcriptional level by db-cAMP. To assess the increase in PDE4B2 and PDE4D1/D2 mRNA expression, the promoters containing these genes were characterized. Transcription from both promoters was stimulated by db-cAMP. Because chronic antidepressant treatment increases PDE4B, and not PDE4D, mRNA expression, we focused on the regulation of the PDE4B2 promoter by cAMP and CREB. Dominant negative mutants of CREB suppressed PDE4B2 promoter activity and a constitutively active form of CREB robustly stimulated it. These data demonstrate that in cortical neurons, a short PDE4B2 intronic promoter is regulated by CREB, confers cAMP responsitivity and directs PDE4B2 mRNA and protein expression.