title: GSK3 and KIF5 regulate activity-dependent sorting of gephyrin between axons and dendrites.
abstract: The kinesin KIF5 transports neuronal cargoes into axons and dendrites. Isolated KIF5 motor domains preferentially move into axons, however KIF5 binding to GRIP1 or gephyrin drives the motor into dendrites, to deliver AMPA receptors (AMPARs) or glycine receptors (GlyRs), respectively. At postsynaptic sites, gephyrin forms a multimeric scaffold to anchor GlyRs and GABAA receptors (GABAARs) in apposition to inhibitory presynaptic terminals. Here, we report the unexpected observation that increased intracellular calcium through chronic activation of AMPARs, steers a newly synthesized gephyrin fusion protein (tomato-gephyrin) to axons and interferes with its normal delivery into dendrites of cultured neurons. Axonal gephyrin clusters were not apposed to presynaptic terminals, but colocalized with GlyRs and neuroligin-2 (NLG2). Notably, functional blockade of glycogen synthase kinase-3 (GSK3) and KIF5 normalized gephyrin missorting into the axonal compartment. In contrast, mutagenesis of gephyrin S270, a GSK3 target, did not contribute to axo-dendritic sorting. Our data are consistent with previous observations, which report regulation of kinesin motility through GSK3 activity. They suggest that GSK3 regulates the sorting of GlyR/gephyrin and NLG2 complexes in a KIF5-dependent manner.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Louisa
authors.initials: L
authors.lastname: Rathgeber
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Kira V
authors.initials: KV
authors.lastname: Gromova
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Schaefer
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Breiden
authors.affiliation: Division of Neurophysiology, University of Hamburg, Martin-Luther-King Platz 3, 20146 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lohr
authors.affiliation: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Falkenried 94, 20251 Hamburg, Germany. Electronic address: matthias.kneussel@zmnh.uni-hamburg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C507512:Kif5A protein, mouse; D008565:Membrane Proteins; D011994:Recombinant Proteins; C073441:gephyrin; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins; D002118:Calcium
keywords: AMPA; Axon; Dendrite; GABA(A) receptor; GSK3; Gephyrin; Glycine receptor; Inhibitory synapse; KIF5; Kinesin; Neuroligin; Neuron; Sorting