title: Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons.
abstract: Neuronal activity results in long lasting changes in synaptic structure and function by regulating mRNA translation in dendrites. These activity dependent events yield the synthesis of proteins known to be important for synaptic modifications and diverse forms of synaptic plasticity. Worthy of note, there is accumulating evidence that the eukaryotic Elongation Factor 2 Kinase (eEF2K)/eukaryotic Elongation Factor 2 (eEF2) pathway may be strongly involved in this process. Upon activation, eEF2K phosphorylates and thereby inhibits eEF2, resulting in a dramatic reduction of mRNA translation. eEF2K is activated by elevated levels of calcium and binding of Calmodulin (CaM), hence its alternative name calcium/CaM-dependent protein kinase III (CaMKIII). In dendrites, this process depends on glutamate signaling and N-methyl-D-aspartate receptor (NMDAR) activation. Interestingly, it has been shown that eEF2K can be activated in dendrites by metabotropic glutamate receptor (mGluR) 1/5 signaling, as well. Therefore, neuronal activity can induce local proteomic changes at the postsynapse by altering eEF2K activity. Well-established targets of eEF2K in dendrites include brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), the alpha subunit of calcium/CaM-dependent protein kinase II (αCaMKII), and microtubule-associated protein 1B (MAP1B), all of which have well-known functions in different forms of synaptic plasticity. In this review we will give an overview of the involvement of the eEF2K/eEF2 pathway at dendrites in regulating the translation of dendritic mRNA in the context of altered NMDAR- and neuronal activity, and diverse forms of synaptic plasticity, such as metabotropic glutamate receptor-dependent-long-term depression (mGluR-LTD). For this, we draw on studies carried out both in vitro and in vivo.
authors.affiliation: CNR Institute of Neuroscience and Department of Biotechnology and Translational Medicine, University of Milan Milan, Italy.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heise
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: CNR Institute of Neuroscience and Department of Biotechnology and Translational Medicine, University of Milan Milan, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Culotta
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: di Luca
authors.affiliation: CNR Institute of Neuroscience and Department of Biotechnology and Translational Medicine, University of Milan Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Verpelli
authors.affiliation: CNR Institute of Neuroscience and Department of Biotechnology and Translational Medicine, University of Milan Milan, Italy ; Neuromuscular Diseases and Neuroimmunology, Foundation Carlo Besta Neurological Institute Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
keywords: dendrites; eEF2; eEF2K; neurons; synapses; synaptic plasticity; translation