Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism

被引:160
作者
Sasaki, M
Gonzalez-Zulueta, M
Huang, H
Herring, WJ
Ahn, SY
Ginty, DD
Dawson, VL
Dawson, TM
机构
[1] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA
[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA
[3] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21287 USA
关键词
D O I
10.1073/pnas.97.15.8617
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Neuronal nitric oxide (NO) synthase (nNOS) is dynamically regulated in response to a variety of physiologic and pathologic stimuli. Although the dynamic regulation of nNOS is well established, the molecular mechanisms by which such diverse stimuli regulate nNOS expression have not yet been identified. We describe experiments demonstrating that Ca2+ entry through voltage-sensitive Ca2+ channels regulates nNOS expression through alternate promoter usage in cortical neurons and that nNOS exon 2 contains the regulatory sequences that respond to Ca2+. Deletion and mutational analysis of the nNOS exon 2 promoter reveals two critical cAMP/Ca2+ response elements (CREs) that are immediately upstream of the transcription start site. CREB binds to the CREs within the nNOS gene. Mutation of the nNOS CREs as well as blockade of CREB function results in a dramatic loss of nNOS transcription. These findings suggest that nNOS is a Ca2+-regulated gene through the interactions of CREB on the CREs within the nNOS exon 2 promoter and that these interactions are likely to be centrally involved in the regulation of nNOS in response to neuronal injury and activity-dependent plasticity.
引用
收藏
页码:8617 / 8622
页数:6
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