Nitric oxide and histone deacetylases: A new relationship between old molecules

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from a range of nuclear and cytoplasmic proteins. Recently, we described a novel route to neurotrophin-dependent gene activation in neurons, which requires the S-nitrosylation of nuclear HDAC2 by the gaseous molecule nitric oxide (NO).1 We have further investigated the NO-dependent regulation of HDACs in neurons. Using a fluorogenic deacetylation assay, we show that NO decreases the enzymatic activity of a subgroup of neuronal HDACs in vitro and that this inhibition is not due to damaging modifications such as oxidation or tyrosine nitration. The neuronal HDACs whose catalytic activity is inhibited by NO are entirely those that are localized in the cytoplasm. These observations support and extend the concept that nitric oxide is a key regulator of HDAC function in mammalian neurons.