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 journalArticlepeer-review


Many neuronal processes require gene activation by synaptically evoked Ca(2+) transients. Ca(2+)-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 Ca(2+)-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
Pages (from-to)171-85
Number of pages15
JournalJournal of Neurochemistry
Issue number1
Publication statusPublished - 2005


  • 4-Aminopyridine
  • Aniline Compounds
  • Animals
  • Bicuculline
  • Calcium
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Nucleus
  • Cells, Cultured
  • DNA-Binding Proteins
  • Diagnostic Imaging
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors
  • Fluorescent Antibody Technique
  • GABA Antagonists
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Hippocampus
  • Histone Deacetylases
  • Hormones
  • Hydroxamic Acids
  • Membrane Proteins
  • Neurons
  • Nuclear Receptor Co-Repressor 2
  • Okadaic Acid
  • Potassium Channel Blockers
  • Protein Synthesis Inhibitors
  • Receptors, Notch
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Repressor Proteins
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tretinoin
  • Xanthenes

Cite this