Role of ERK signaling in activity-dependent modifications of histone proteins.

It is well-established that neuronal intracellular signaling governed by the extracellular signal-regulated kinase (ERK/MAPK) plays a crucial role in long-term adaptive changes that occur during cognitive processes. ERK is a downstream component of a conserved signaling module that is activated by the serine/threonine kinase, Raf, which activates the MAPK/ERK kinase (MEK)1/2 protein kinases, which, in turn, activate ERK1/2. This signaling pathway has been reported to be activated in numerous physiological conditions due to a variety of stimuli, ranging from the activation of ionotropic glutamatergic receptors to metabotropic dopaminergic receptors and neurotrophin receptors. Interestingly, activated ERK can have early and late downstream effects at both the nuclear and synaptic levels. Locally, ERK signaling results in transient changes in the efficacy of synaptic transmission by modifying both pre- and post-synaptic targets. Once translocated into the nucleus, ERK signaling may control transcription by targeting several different regulators of gene expression such as transcription factors and histone proteins. ERK function is considered fundamental in processes such as long-term memory storage and drug addiction, by means of its role in activity-dependent epigenetic modifications that occur in the brain. In this review, we summarize the current understanding of ERK action in the neuroepigenetic processes underlying physiological responses, cognitive processes and drug addiction.