title: G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants.
abstract: Antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been widely used for the treatment of not only depression but also other psychiatric disorders, although the molecular mechanisms of the drug effects have not yet been sufficiently revealed. Here, we investigated the in vivo effects of these antidepressants on G protein-activated inwardly rectifying K+ (GIRK) channels, which are important for regulating the excitability of various cells, by using weaver (wv) mice, which have mutant GIRK channels and show abnormal neuronal cell death and motor disturbances. First, we found that a widely used SSRI fluoxetine (also known as Prozac) effectively inhibited wv GIRK2 channels like wild-type GIRK channels, expressed in Xenopus oocytes. Next, we found that weaver motor disturbances were remarkably alleviated by chronic treatment with fluoxetine or desipramine. Furthermore, the chronic fluoxetine treatment substantially suppressed the abnormal neuronal cell death in the weaver mouse cerebellum and pontine nuclei. These results suggest that continuous inhibition of wv GIRK2 channels by a group of antidepressants caused substantial suppression of the neuronal cell death and resulted in improvement of motor abilities in weaver mice. These results provide evidence for in vivo GIRK channel inhibition by a group of antidepressants.
authors.affiliation: Division of Psychobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa Setagaya, Tokyo 156-8585, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.forename: Toru
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Miwako
authors.initials: M
authors.lastname: Ozaki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takamatsu
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Ogai
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Hideko
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008818:Mice, Neurologic Mutants; D009069:Movement Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014981:Xenopus
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D005473:Fluoxetine; D019204:GTP-Binding Proteins; D003891:Desipramine