title: Activation of sodium-dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin-dependent kinase IIβ's actin-binding/-stabilizing domain.
abstract: Signaling via the major excitatory amino acid glutamate has been implicated in the regulation of various aspects of the biology of oligodendrocytes, the myelinating cells of the central nervous system (CNS). In this respect, cells of the oligodendrocyte lineage have been described to express a variety of glutamate-responsive transmembrane proteins including sodium-dependent glutamate transporters. The latter have been well characterized to mediate glutamate clearance from the extracellular space. However, there is increasing evidence that they also mediate glutamate-induced intracellular signaling events. Our data presented here show that the activation of oligodendrocyte expressed sodium-dependent glutamate transporters, in particular GLT-1 and GLAST, promotes the morphological aspects of oligodendrocyte maturation. This effect was found to be associated with a transient increase in intracellular calcium levels and a transient phosphorylation event at the serine (S)(371) site of the calcium sensor calcium/calmodulin-dependent kinase type IIβ (CaMKIIβ). The potential regulatory S(371) site is located within CaMKIIβ's previously defined actin-binding/-stabilizing domain, and phosphorylation events within this domain were identified in our studies as a requirement for sodium-dependent glutamate transporter-mediated promotion of oligodendrocyte maturation. Furthermore, our data provide good evidence for a role of these phosphorylation events in mediating detachment of CaMKIIβ from filamentous (F)-actin, and hence allowing a remodeling of the oligodendrocyte's actin cytoskeleton. Taken together with our recent findings, which demonstrated a crucial role of CaMKIIβ in regulating CNS myelination in vivo, our data strongly suggest that a sodium-dependent glutamate transporter-CaMKIIβ-actin cytoskeleton axis plays an important role in the regulation of oligodendrocyte maturation and CNS myelination.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.|Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F, México.
authors.forename: Zila
authors.initials: Z
authors.lastname: Martinez-Lozada
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Waggener
authors.affiliation: Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Karam
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.|Saitama University Brain Science Institute, Saitama University, Saitama 338-8570, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F, México.
authors.forename: Arturo
authors.initials: A
authors.lastname: Ortega
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.
authors.forename: Babette
authors.initials: B
authors.lastname: Fuss
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
chemical_list: D000199:Actins; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; D018698:Glutamic Acid; D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517676:Camk2b protein, rat; D002118:Calcium
keywords: actin cytoskeleton; calcium signaling; central nervous system; differentiation; myelin