Nuclear calcium signaling regulates nuclear export of a subset of class IIa histone deacetylases following synaptic activity.
In neurons, dynamic changes in the subcellular localization of histone deacetylases (HDACs) are thought to contribute to signal-regulated gene expression. Here we show that in mouse hippocampal neurons, synaptic activity-dependent nucleo-cytoplasmic shuttling is a common feature of all members of class IIa HDACs, which distinguishes them from other classes of HDACs. Nuclear calcium, a key regulator in neuronal gene expression, is required for the nuclear export of a subset of class IIa HDACs. We found that inhibition of nuclear calcium signaling using CaMBP4 or increasing the nuclear calcium buffering capacity by means of expression of a nuclear targeted version of parvalbumin (PV.NLS-mC) led to a build-up of HDAC4 and HDAC5 in the cell nucleus, which in the case of PV.NLS-mC can be reversed by nuclear calcium transients triggered by bursts of action potential firing. A similar nuclear accumulation of HDAC4 and HDAC5 was observed in vivo in the mouse hippocampus following stereotaxic delivery of recombinant adeno-associated viruses expressing either CaMBP4 or PV.NLS-mC. The modulation of HDAC4 activity either by RNA interference-mediated reduction of HDAC4 protein levels or by expression of a constitutively nuclear localized mutant of HDAC4 leads to changes in the mRNA levels of several nuclear calcium-regulated genes with known functions in acquired neuroprotection (atf3, serpinb2), memory consolidation (homer1, arc), and the development of chronic pain (ptgs2, c1qc). These results identify nuclear calcium as a regulator of nuclear export of HDAC4 and HDAC5. The reduction of nuclear localized HDACs represents a novel transcription-promoting pathway stimulated by nuclear calcium.
Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364 69120 Heidelberg, Germany.
Friederike
F
Schlumm
Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364 69120 Heidelberg, Germany.
Daniela
D
Mauceri
Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364 69120 Heidelberg, Germany.
H Eckehard
HE
Freitag
Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364 69120 Heidelberg, Germany. Electronic address: hilmar.bading@uni-hd.de.
Hilmar
H
Bading
D021581:Active Transport, Cell Nucleus; D019943:Amino Acid Substitution; D000818:Animals; D020013:Calcium Signaling; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D015870:Gene Expression; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology; D010320:Parvalbumins / Q000494:pharmacology; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D010320:Parvalbumins; D012097:Repressor Proteins; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases