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

Masayuki Sasaki, Mirella Gonzalez-Zulueta, Hui Huang, William J. Herring, Sohyun Ahn, David D. Ginty, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8617-8622
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number15
DOIs
StatePublished - Jul 18 2000

ASJC Scopus subject areas

  • General

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