Diffusion and not active transport underlies and limits ERK1/2 synapse-to-nucleus signaling in hippocampal neurons.
The propagation of signals from synapses and dendrites to the nucleus is crucial for long lasting adaptive changes in the nervous system. The ERK-MAPK pathway can link neuronal activity and cell surface receptor activation to the regulation of gene transcription, and it is often considered the principal mediator of synapse-to-nucleus communication in late-phase plasticity and learning. However, the mechanisms underlying ERK1/2 trafficking in dendrites and nuclear translocation in neurons remain to be determined leaving it unclear whether ERK1/2 activated at the synapse can contribute to nuclear signaling and transcriptional regulation. Using the photobleachable and photoactivable fluorescent tag Dronpa on ERK1 and ERK2, we show here that ERK1/2 translocation to the nucleus of hippocampal neurons is induced by the stimulation of N-methyl-D-aspartate receptors or TrkB stimulation and is apparently mediated by facilitated diffusion. In contrast, ERK1/2 trafficking within dendrites is not signal-regulated and is mediated by passive diffusion. Within dendrites, the reach of a locally activated pool of ERK1/2 is very limited and follows an exponential decay with distance. These results indicate that successful signal propagation to the nucleus by the ERK-MAPK pathway depends on the distance of the nucleus from the site of ERK1/2 activation. ERK1/2 activated within or near the soma may rapidly reach the nucleus to induce gene expression, whereas ERK1/2 activated at distal synapses may only contribute to local signaling.
Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, 69120 Heidelberg, Germany.
J Simon
JS
Wiegert
C Peter
CP
Bengtson
Hilmar
H
Bading
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001692:Biological Transport; D001693:Biological Transport, Active; D002467:Cell Nucleus / Q000378:metabolism*; D004058:Diffusion; D006624:Hippocampus / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3