RGD Reference Report - A kinesin signaling complex mediates the ability of GSK-3beta to affect mood-associated behaviors. - Rat Genome Database

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A kinesin signaling complex mediates the ability of GSK-3beta to affect mood-associated behaviors.

Authors: Du, Jing  Wei, Yanling  Liu, Lidong  Wang, Yun  Khairova, Rushaniya  Blumenthal, Rayah  Tragon, Tyson  Hunsberger, Joshua G  Machado-Vieira, Rodrigo  Drevets, Wayne  Wang, Yu Tian  Manji, Husseini K 
Citation: Du J, etal., Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11573-8. doi: 10.1073/pnas.0913138107. Epub 2010 Jun 7.
RGD ID: 13432347
Pubmed: PMID:20534517   (View Abstract at PubMed)
PMCID: PMC2895136   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0913138107   (Journal Full-text)

Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3beta, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3beta capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:B2GV7413432347PMID:20534517IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Gria1  (glutamate ionotropic receptor AMPA type subunit 1)

Objects referenced in this article
Gene Klc2 kinesin light chain 2 Rattus norvegicus

Additional Information