title: Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin.
abstract: The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells.
  
  
  CONCLUSIONS
  We identified and cloned a family of three inositol hexakisphosphate kinases (IP6Ks) that generate the inositol pyrophosphates, most notably 5-diphosphoinositol pentakisphosphate (IP7). Of these, IP6K3 has been least characterized. In the present study we generated IP6K3 knock-out mice and show that IP6K3 is highly expressed in cerebellar Purkinje cells. IP6K3-deleted mice display defects of motor learning and coordination. IP6K3-null mice manifest aberrations of Purkinje cells with a diminished number of synapses. IP6K3 interacts with the cytoskeletal proteins spectrin and adducin whose altered disposition in IP6K3 knock-out mice may mediate phenotypic features of the mutant mice. These findings afford molecular/cytoskeletal mechanisms by which the inositol polyphosphate system impacts brain function.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Chenglai
authors.initials: C
authors.lastname: Fu
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Departments of Pharmacology and Molecular Sciences, and.
authors.forename: Ruo-Jing
authors.initials: RJ
authors.lastname: Li
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Joshua A
authors.identifier: http://orcid.org/0000-0002-7078-0175
authors.initials: JA
authors.lastname: Crawford
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: A Basit
authors.initials: AB
authors.lastname: Khan
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Ting Martin
authors.initials: TM
authors.lastname: Ma
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Jiyoung Y
authors.initials: JY
authors.lastname: Cha
authors.affiliation: The Solomon H. Snyder Department of Neuroscience.
authors.forename: Adele M
authors.initials: AM
authors.lastname: Snowman
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Departments of Pharmacology and Molecular Sciences, and Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 ssnyder@jhmi.edu.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D048430:Cell Shape / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism*; D013049:Spectrin / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; D017856:Phosphotransferases (Phosphate Group Acceptor); D013049:Spectrin; D000099291:Adducins
keywords: IP6K; Purkinje cell; adducin; cerebellar synapse; kinase independent; spectrin