when spontaneous electrical activity occurred it was sufficient to cause nuclear export of the histone deacetylase HDAC4. Another histone deacetylase, HDAC5, was translocated to the cytoplasm after stimulation of calcium flux through synaptic NMDA receptors. Of 4,407 proteins found in the nuclei of rat forebrain neurons in culture, after activation of the neurons, 2,860 changed in nuclear concentration due to nucleocytoplasmic shuttling or sythesis or degradation of the proteins. After neuronal stimulation, of all proteins, HDAC4 had the largest concentration decrease, due to shuttling out of the nucleus. A decrease in a HDAC would cause greater presence of acetylation on histone tails. Histone acetylation is associated with active transcription of genes, (see top figure in this section) and decrease in a histone deacetylase would have epigenetic effects by likely maintaining or increasing gene transcriptions. The large decrease in HDAC4 after neuron activation may have a similarly large effect on neuronal function. Non-histone effects It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by post-translational modifications. Protein phosphorylation is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinases or dephosphorylated by the action of phosphatases. The acetylation of lysine residues is emerging as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases. It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are transcription factors and co-regulators, some are not. Note the following four examples: HDAC6 is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitination and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction. HDAC6 is important regulator of HSP90 function and its inhibitor proposed to treat metabolic disorders. PTEN is an important phosphatase involved in cell signaling via phosphoinositols and the AKT/PI3 kinase pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (PCAF) can repress its activity; on the