title: AMIGO-Kv2.1 Potassium Channel Complex Is Associated With Schizophrenia-Related Phenotypes.
abstract: The enormous variability in electrical properties of neurons is largely affected by a multitude of potassium channel subunits. Kv2.1 is a widely expressed voltage-dependent potassium channel and an important regulator of neuronal excitability. The Kv2.1 auxiliary subunit AMIGO constitutes an integral part of the Kv2.1 channel complex in brain and regulates the activity of the channel. AMIGO and Kv2.1 localize to the distinct somatodendritic clusters at the neuronal plasma membrane. Here we have created and characterized a mouse line lacking the AMIGO gene. Absence of AMIGO clearly reduced the amount of the Kv2.1 channel protein in mouse brain and altered the electrophysiological properties of neurons. These changes were accompanied by behavioral and pharmacological abnormalities reminiscent of those identified in schizophrenia. Concomitantly, we have detected an association of a rare, population-specific polymorphism of KV2.1 (KCNB1) with human schizophrenia in a genetic isolate enriched with schizophrenia. Our study demonstrates the involvement of AMIGO-Kv2.1 channel complex in schizophrenia-related behavioral domains in mice and identifies KV2.1 (KCNB1) as a strong susceptibility gene for schizophrenia spectrum disorders in humans.
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland; marjaana.kiiltomaki@helsinki.fi.
authors.forename: Marjaana A
authors.initials: MA
authors.lastname: Peltola
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland;
authors.forename: Juha
authors.initials: J
authors.lastname: Kuja-Panula
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland;
authors.forename: Johanna
authors.initials: J
authors.lastname: Liuhanen
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland;
authors.forename: Vootele
authors.initials: V
authors.lastname: Võikar
authors.affiliation: Division of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland;
authors.forename: Petteri
authors.initials: P
authors.lastname: Piepponen
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Tero
authors.initials: T
authors.lastname: Hiekkalinna
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland;
authors.forename: Tomi
authors.initials: T
authors.lastname: Taira
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland;
authors.forename: Sari E
authors.initials: SE
authors.lastname: Lauri
authors.affiliation: Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland;
authors.forename: Jaana
authors.initials: J
authors.lastname: Suvisaari
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland;
authors.forename: Natalia
authors.initials: N
authors.lastname: Kulesskaya
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland;
authors.forename: Heikki
authors.initials: H
authors.lastname: Rauvala
mesh_terms: D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006220:Haloperidol / Q000494:pharmacology; D006360:Heat-Shock Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D051669:Shab Potassium Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: C570804:AMIGO protein, mouse; C571087:AMIGO1 protein, human; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D006360:Heat-Shock Proteins; C496988:KCNB1 protein, human; C496990:Kcnb1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D051669:Shab Potassium Channels; C063820:SNP nonapeptide; D012701:Serotonin; D016291:Dizocilpine Maleate; D003024:Clozapine; D006220:Haloperidol
keywords: AMIGO; KCNB1; Kv2.1; mouse behavior; susceptibility gene