{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T21:40:30Z","timestamp":1785879630848,"version":"3.56.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,6,22]]},"abstract":"<jats:p>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 \u03b1-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-3\u03b2, 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-3\u03b2 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.<\/jats:p>","DOI":"10.1073\/pnas.0913138107","type":"journal-article","created":{"date-parts":[[2010,6,7]],"date-time":"2010-06-07T20:17:25Z","timestamp":1275941845000},"page":"11573-11578","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":108,"title":["A kinesin signaling complex mediates the ability of GSK-3\u03b2 to affect mood-associated behaviors"],"prefix":"10.1073","volume":"107","author":[{"given":"Jing","family":"Du","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Wei","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brain Research Centre, Vancouver Coastal Health Research Institute and University of British Columbia, Vancouver, BC, V6T 2B5 Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rushaniya","family":"Khairova","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayah","family":"Blumenthal","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyson","family":"Tragon","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua G.","family":"Hunsberger","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Machado-Vieira","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Drevets","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Tian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brain Research Centre, Vancouver Coastal Health Research Institute and University of British Columbia, Vancouver, BC, V6T 2B5 Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husseini K.","family":"Manji","sequence":"additional","affiliation":[{"name":"Johnson and Johnson Pharmaceuticals Group, Titusville, NJ 08560"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,6,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-977X(03)00078-6"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.16.8455"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2007.06.017"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(01)00011-9"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145704004535"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4753-03.2004"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3080-07.2008"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301178"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.09.017"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(00)00194-5"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.029"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.14.1.59"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)81067-3"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature743"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4603-04.2005"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/81823"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/35016089"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5421.1811"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.011008.145634"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.12.11.1443"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.015"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(02)02289-0"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(01)02184-5"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600240"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.24.14112"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808401200"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.05.025"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.3.281"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-12-04188.2001"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2007.04.002"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2007.11.002"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.06.075"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2007.03.003"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03033801"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(03)00117-3"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1258-04.2004"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812671106"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1997.78.5.2569"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0913138107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:48:58Z","timestamp":1649789338000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0913138107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,6,7]]},"references-count":38,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2010,6,22]]}},"alternative-id":["10.1073\/pnas.0913138107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0913138107","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.4150960.3933059","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,6,7]]},"assertion":[{"value":"2010-06-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}