Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness

Grahame J. McKenzie, Patrick Stevenson, George Ward, Sofia Papadia, Hilmar Bading, Sangeeta Chawla, Martin Privalsky, Giles E. Hardingham

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Many neuronal processes require gene activation by synaptically evoked Ca2+ transients. Ca2+-dependent signal pathways activate some transcription factors outright, but here we report that such signals also potentiate the activation of nuclear receptors by their cognate hormone, and of CBF1 by Notch, transcription factors hitherto not thought to be Ca 2+-responsive. This potentiation is occluded by histone deacetylase inhibition, indicating a mechanism involving inactivation of co-repressors associated with these transcription factors. Synaptic activity, acting via the nuclear Ca2+-dependent activation of CaM kinase IV, triggers the disruption of subnuclear domains containing class II histone deacetylases (HDACs) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a broad-specificity co-repressor which represses nuclear hormone receptors and CBF1. The sequential loss of class II HDACs and SMRT from the subnuclear domains, followed by nuclear export, is associated with disruption of SMRT interaction with its target transcription factors and sensitization of these factors to their activating signal. Counterbalancing these changes, protein phosphatase 1 promotes nuclear localization of SMRT and inactivation of nuclear receptors and CBF1. Thus, the synaptically controlled kinase-phosphatase balance of the neuron determines the efficacy of SMRT-mediated repression and the signal-responsiveness of a variety of transcription factors.

Original languageEnglish (US)
Pages (from-to)171-185
Number of pages15
JournalJournal of Neurochemistry
Volume93
Issue number1
DOIs
StatePublished - Apr 2005

Keywords

  • Calcium signalling
  • Calcium-calmodulin-dependent protein kinase
  • Mitogen-activated protein kinases
  • Nuclear hormone receptors
  • SMRT

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    McKenzie, G. J., Stevenson, P., Ward, G., Papadia, S., Bading, H., Chawla, S., Privalsky, M., & Hardingham, G. E. (2005). Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness. Journal of Neurochemistry, 93(1), 171-185. https://doi.org/10.1111/j.1471-4159.2005.03010.x