title: KCC2 regulates actin dynamics in dendritic spines via interaction with β-PIX.
abstract: Chloride extrusion in mature neurons is largely mediated by the neuron-specific potassium-chloride cotransporter KCC2. In addition, independently of its chloride transport function, KCC2 regulates the development and morphology of dendritic spines through structural interactions with the actin cytoskeleton. The mechanism of this effect remains largely unknown. In this paper, we show a novel pathway for KCC2-mediated regulation of the actin cytoskeleton in neurons. We found that KCC2, through interaction with the b isoform of Rac/Cdc42 guanine nucleotide exchange factor β-PIX, regulates the activity of Rac1 GTPase and the phosphorylation of one of the major actin-regulating proteins, cofilin-1. KCC2-deficient neurons had abnormally high levels of phosphorylated cofilin-1. Consistently, dendritic spines of these neurons exhibited a large pool of stable actin, resulting in reduced spine motility and diminished density of functional synapses. In conclusion, we describe a novel signaling pathway that couples KCC2 to the cytoskeleton and regulates the formation of glutamatergic synapses.
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Olaya
authors.initials: O
authors.lastname: Llano
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Sergey
authors.initials: S
authors.lastname: Smirnov
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Shetal
authors.initials: S
authors.lastname: Soni
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Andrey
authors.initials: A
authors.lastname: Golubtsov
authors.affiliation: Neurogenetics group, Center of Excellence Hearing4All, School of Medicine and Health Sciences and Research Center for Neurosensory Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Guillemin
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Pirta
authors.initials: P
authors.lastname: Hotulainen
authors.affiliation: Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France Aix-Marseille Université, Unité Mixte de Recherche 901, 13273 Marseille, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Medina
authors.affiliation: Neurogenetics group, Center of Excellence Hearing4All, School of Medicine and Health Sciences and Research Center for Neurosensory Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
authors.forename: Hans Gerd
authors.initials: HG
authors.lastname: Nothwang
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France Aix-Marseille Université, Unité Mixte de Recherche 901, 13273 Marseille, France claudio.rivera@helsinki.fi anastasia.ludwig@helsinki.fi.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
authors.affiliation: Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland claudio.rivera@helsinki.fi anastasia.ludwig@helsinki.fi.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D051338:Cofilin 1; D064067:Rho Guanine Nucleotide Exchange Factors; D027981:Symporters; D000096922:K Cl- Cotransporters; C495811:Cfl1 protein, mouse