Neuronal activity‐dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5

Abstract

The class II histone deacetylases, HDAC4 and HDAC5, directly bind to and repress myogenic transcription factors of the myocyte enhancer factor-2 (MEF-2) family thereby inhibiting skeletal myogenesis. During muscle differentiation, repression of gene transcription by MEF-2/HDAC complexes is relieved due to calcium/calmodulin-dependent (CaM) kinase-induced translocation of HDAC4 and HDAC5 to the cytoplasm. MEF-2 proteins and HDACs are also highly expressed in the nervous system and have been implicated in neuronal survival and differentiation. Here we investigated the possibility that the subcellular localization of HDACs, and thus their ability to repress target genes, is controlled by synaptic activity in neurones. We found that, in cultured hippocampal neurones, the localization of HDAC4 and HDAC5 is dynamic and signal-regulated. Spontaneous electrical activity was sufficient for nuclear export of HDAC4 but not of HDAC5. HDAC5 translocation to the cytoplasm was induced following stimulation of calcium flux through synaptic NMDA receptors or L-type calcium channels; glutamate bath application (stimulating synaptic and extrasynaptic NMDA receptors) antagonized nuclear export. Activity-induced nucleocytoplasmic shuttling of both HDACs was partially blocked by the CaM kinase inhibitor KN-62 with HDAC5 nuclear export being more sensitive to CaM kinase inhibition than that of HDAC4. Thus, the subcellular localization of HDACs in neurones is specified by neuronal activity; differences in the activation thresholds for HDAC4 and HDAC5 nuclear export provides a mechanism for input-specific gene expression.

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

“…The results of the present work further substantiate HDAC4 as a specific direct substrate of CaMKII␦, based on the finding that HDAC4 phosphorylation was abolished in cardiac extracts from CaMKII␦-KO mice, whereas HDAC5 phosphorylation was unaffected. Others have reported that CaMKII induces cytosolic accumulation of both HDAC4 and HDAC5 (19,37,38). Because HDAC5 can acquire CaMKII responsiveness by oligomerization with HDAC4 (20), the nuclear export of HDAC5 in response to CaMKII signaling may reflect, at least in part, this type of indirect mechanism of HDAC5 regulation.…”

Class IIa histone deacetylases: regulating the regulators

“…Whereas neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5 was induced through both L-type calcium channels and synaptic N-methyl-Daspartic acid receptors, differences in the activation thresholds for HDAC4 and HDAC5 nuclear export were observed (Chawla et al, 2003). Another neuronal signaling pathway converges on class IIa HDACs.…”

“…This diversity allows class IIa HDACs to respond to different signaling pathways, with each signaling pathway providing a functional relevance for a given kinase. Some kinases have been shown to act preferentially on specific members of the class IIa family, which emphasizes the importance that distinct class IIa HDACs may have in specific genetic programs (Chawla et al, 2003;Liu et al, 2005;. CaMKII, for example, is able to drive HDAC4, but not HDAC5, out of the nucleus, probably because HDAC4 possesses a nonconserved CaMKII-binding site (Backs et al, 2006).…”

Nuclear export of BRCA1 occurs during early S phase and is calcium-dependent

“…In addition to regulating the cell cycle, calcium signaling also can regulate the nuclear transport of proteins. For example, increases in intracellular calcium result in translocation of histone deacetylase 5 (HDAC5) from the nucleus to the cytoplasm in cultured hippocampal neurons [17]. In contrast, increases in intracellular calcium result in nuclear accumulation of human transducer of regulated CREB (TORC) proteins [18] and nuclear factor of activated T-cells (NF-AT) [19].…”