title: Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß.
abstract: BACKGROUND
  The Na+,Cl- coupled creatine transporter CreaT (SLC6A8) is expressed in a variety of tissues including the brain. Genetic defects of CreaT lead to mental retardation with seizures. The present study explored the regulation of CreaT by the ubiquitously expressed glycogen synthase kinase GSK3ß, which contributes to the regulation of neuroexcitation. GSK3ß is phosphorylated and thus inhibited by PKB/Akt. Moreover, GSK3ß is inhibited by the antidepressant lithium. The present study thus further tested for the effects of PKB/Akt and of lithium.
  
  
  METHODS
  CreaT was expressed in Xenopus laevis oocytes with or without wild-type GSK3ß or inactive K85RGSK3ß. CreaT and GSK3ß were further expressed without and with additional expression of wild type PKB/Akt. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp.
  
  
  RESULTS
  Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes, co-expression of GSK3ß but not of K85RGSK3ß, resulted in a significant decrease of creatine induced current. Kinetic analysis revealed that GSK3ß significantly decreased the maximal creatine transport rate. Exposure of CreaT and GSK3ß expressing oocytes for 24 hours to Lithium was followed by a significant increase of the creatine induced current. The effect of GSK3ß on CreaT was abolished by co-expression of PKB/Akt.
  
  
  CONCLUSIONS
  GSK3ß down-regulates the creatine transporter CreaT, an effect reversed by treatment with the antidepressant Lithium and by co-expression of PKB/Akt.
authors.affiliation: Department of Physiology I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fezai
authors.forename: Mohamed
authors.initials: M
authors.lastname: Jemaà
authors.forename: Hajar
authors.initials: H
authors.lastname: Fakhri
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Bhaeldin
authors.initials: B
authors.lastname: Elsir
authors.forename: Lisann
authors.initials: L
authors.lastname: Pelzl
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D015536:Down-Regulation / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014981:Xenopus
chemical_list: D026901:Membrane Transport Proteins; C080679:creatine transporter; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt