Calcineurin activity is required for depolarization-induced, CREB-dependent gene transcription in cortical neurons
Article first published online: 11 JUL 2007
© 2007 The Authors. Journal Compilation © 2007 International Society for Neurochemistry
Journal of Neurochemistry
Volume 103, Issue 2, pages 761–770, October 2007
How to Cite
Kingsbury, T. J., Bambrick, L. L., Roby, C. D. and Krueger, B. K. (2007), Calcineurin activity is required for depolarization-induced, CREB-dependent gene transcription in cortical neurons. Journal of Neurochemistry, 103: 761–770. doi: 10.1111/j.1471-4159.2007.04801.x
- Issue published online: 11 JUL 2007
- Article first published online: 11 JUL 2007
- Received May 2, 2007; revised manuscript received June 7, 2007; accepted June 7, 2007.
- activity-dependent transcription;
- cyclic AMP;
- cyclic AMP response element binding protein;
Cyclic AMP response element binding protein (CREB) functions as an activity-dependent transcription factor in the nervous system. Increases in intracellular Ca2+ due to neuronal activity lead to the phosphorylation and subsequent activation of CREB. Although phosphorylation of CREB at Ser-133 is necessary for the stimulation of transcriptional activity, it is not sufficient. Here we demonstrate that in mouse cortical neurons, inhibition of the Ca2+-dependent protein phosphatase calcineurin by FK506 or cyclosporine A blocks CREB-dependent gene expression induced by depolarization without inhibiting depolarization-induced Ca2+ influx or CREB Ser-133 phosphorylation. Over-expression of a constitutively-active allele of the transducer of regulated CREB activity could not bypass the requirement for calcineurin activity. Stimulation of a CRE-luciferase reporter gene by depolarization was sensitive to FK506 throughout the entire time course of the transcriptional response, revealing that calcineurin activity is required to maintain CREB-dependent transcription. Stimulation of CRE-luciferase expression by forskolin and 8-Br-cAMP also required calcineurin activity. These results suggest that calcineurin functions as a critical determinant in shaping genome responses to CREB activation in cortical neurons.