A kinesin signaling complex mediates the ability of GSK-3beta to affect mood-associated behaviors.
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.
Du
Jing
J
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. duj@mail.nih.gov
Wei
Yanling
Y
Liu
Lidong
L
Wang
Yun
Y
Khairova
Rushaniya
R
Blumenthal
Rayah
R
Tragon
Tyson
T
Hunsberger
Joshua G
JG
Machado-Vieira
Rodrigo
R
Drevets
Wayne
W
Wang
Yu Tian
YT
Manji
Husseini K
HK
D000339:Affect; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009473:Neuronal Plasticity / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D000928:Antidepressive Agents; C000715691:Klc2 protein, mouse; D008869:Microtubule-Associated Proteins; D018091:Receptors, AMPA; D013844:Thiazoles; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins