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

M Sasaki, M Gonzalez-Zulueta… - Proceedings of the …, 2000 - National Acad Sciences
M Sasaki, M Gonzalez-Zulueta, H Huang, WJ Herring, S Ahn, DD Ginty, VL Dawson
Proceedings of the National Academy of Sciences, 2000National Acad Sciences
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 …
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.
National Acad Sciences