TY  - JOUR
PY  - 2010//
TI  - A kinesin signaling complex mediates the ability of GSK-3{beta} to affect mood-associated behaviors
JO  - Proceedings of the National Academy of Sciences of the United States of America
A1  - Du, Jing
A1  - Wei, Y.
A1  - Liu, Lei
A1  - Wang, Yanfu
A1  - Khairova, Rushaniya
A1  - Blumenthal, Rayah
A1  - Tragon, Tyson
A1  - Hunsberger, Joshua G.
A1  - Machado-Vieira, Rodrigo
A1  - Drevets, Wayne
A1  - Wang, Yu Tian
A1  - Manji, Husseini K.
SP  - 11573
EP  - 11578
VL  - 107
IS  - 25
N2  - 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.<p />  <p>Language: en</p>
LA  - en
SN  - 0027-8424
UR  - http://dx.doi.org/10.1073/pnas.0913138107
ID  - ref1
ER  -