View source for GSK-3

{{cs1 config|name-list-style=vanc}}
{{Short description|Class of enzymes}}
{{Infobox protein family
|Name=Glycogen synthase kinase 3, catalytic domain
|Symbol=STKc_GSK3 
|InterPro=IPR039192
|CDD=cd14137
}}
{{infobox protein
|Name= [[GSK3A|glycogen synthase kinase 3 alpha]]
|caption=
|image=
|width=
|HGNCid=4616
|Symbol=[[GSK3A]]
|AltSymbols=
|EntrezGene=2931
|OMIM=606784
|RefSeq=NM_019884
|UniProt=P49840
|PDB=
|ECnumber=2.7.11.26
|Chromosome=19
|Arm=q
|Band=13.2|LocusSupplementaryData=
}}
{{infobox protein
|Name=[[GSK3B|glycogen synthase kinase 3 beta]]
|image= 1J1B.png
|caption=[[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of human GSK-3β (rainbow colored, [[N-terminus]] = blue, [[C-terminus]] = red) bound to phosphoaminophosphonic acid-adenylate ester (spheres).<ref name="pmid14993667">{{PDB|1J1B}}; {{cite journal | vauthors = Aoki M, Yokota T, Sugiura I, Sasaki C, Hasegawa T, Okumura C, Ishiguro K, Kohno T, Sugio S, Matsuzaki T | display-authors = 6 | title = Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 60 | issue = Pt 3 | pages = 439–446 | date = March 2004 | pmid = 14993667 | doi = 10.1107/S090744490302938X | bibcode = 2004AcCrD..60..439A }}</ref>
|width=
|HGNCid=4617
|Symbol=[[GSK3B]]
|AltSymbols=
|EntrezGene=2932
|OMIM=605004
|RefSeq=NM_002093
|UniProt=P49841
|PDB=1Q3W
|PDB_supplemental = [http://www.ebi.ac.uk/pdbe/searchResults.html?display=both&term=P49841 More structures]
|ECnumber=2.7.11.26
|Chromosome=3
|Arm=q
|Band=13.33
|LocusSupplementaryData=
}}
'''Glycogen synthase kinase 3''' ('''GSK-3''') is a [[serine/threonine protein kinase]] that mediates the addition of [[phosphate]] molecules onto [[serine]] and [[threonine]] amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, [[glycogen synthase]] (GS),<ref name="pmid6249596">{{cite journal | vauthors = Embi N, Rylatt DB, Cohen P | title = Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase | journal = European Journal of Biochemistry | volume = 107 | issue = 2 | pages = 519–527 | date = June 1980 | pmid = 6249596 | doi = 10.1111/j.1432-1033.1980.tb06059.x | doi-access = free }}</ref> GSK-3 has since been identified as a [[protein kinase]] for over 100 different proteins in a variety of different pathways.<ref name="pmid25435019 ">{{cite journal | vauthors = Beurel E, Grieco SF, Jope RS | title = Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases | journal = Pharmacology & Therapeutics | volume = 148 | pages = 114–131 | date = April 2015 | pmid = 25435019 | pmc = 4340754 | doi = 10.1016/j.pharmthera.2014.11.016 }}</ref><ref name="pmid15102436">{{cite journal | vauthors = Jope RS, Johnson GV | title = The glamour and gloom of glycogen synthase kinase-3 | journal = Trends in Biochemical Sciences | volume = 29 | issue = 2 | pages = 95–102 | date = February 2004 | pmid = 15102436 | doi = 10.1016/j.tibs.2003.12.004 }}</ref> In mammals, including humans, GSK-3 exists in two [[isozyme]]s encoded by two [[Homology (biology)|homologous]] genes GSK-3α ([[GSK3A]]) and GSK-3β ([[GSK3B]]). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including [[type 2 diabetes]], [[Alzheimer's disease]], [[inflammation]], [[cancer]], [[addiction]]<ref>{{Cite journal | vauthors = Turlik J, Wąsikiewicz E, Domaradzka A, Chrostek G, Gniadzik W, Domagalski M, Duda P |date=December 2021 |title=GSK3β Activity in Reward Circuit Functioning and Addiction |journal=NeuroSci |language=en |volume=2 |issue=4 |pages=443–466 |doi=10.3390/neurosci2040033 |issn=2673-4087|doi-access=free }}</ref> and [[bipolar disorder]].

GSK-3 is a serine/threonine protein kinase that [[phosphorylate]] either [[threonine]] or [[serine]], and this phosphorylation controls a variety of biological activities, such as [[glycogen]] metabolism, [[cell signaling]], [[cellular transport]], and others.<ref>{{cite journal | vauthors = Pandey MK, DeGrado TR | title = Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging | journal = Theranostics | volume = 6 | issue = 4 | pages = 571–593 | year = 2016 | pmid = 26941849 | pmc = 4775866 | doi = 10.7150/thno.14334 }}</ref> GS inhibition by GSK-3β leads to a decrease in glycogen synthesis in the liver and muscles, along with increased blood glucose or hyperglycemia.<ref>{{cite journal | vauthors = Ali A, Hoeflich KP, Woodgett JR | title = Glycogen synthase kinase-3: properties, functions, and regulation | journal = Chemical Reviews | volume = 101 | issue = 8 | pages = 2527–2540 | date = August 2001 | pmid = 11749387 | doi = 10.1021/cr000110o }}</ref> This is why GSK-3β is associated with the pathogenesis and progression of many diseases, such as [[diabetes]], [[obesity]], [[cancer]],<ref>{{cite journal | vauthors = Eldar-Finkelman H | title = Glycogen synthase kinase 3: an emerging therapeutic target | journal = Trends in Molecular Medicine | volume = 8 | issue = 3 | pages = 126–132 | date = March 2002 | pmid = 11879773 | doi = 10.1016/S1471-4914(01)02266-3 }}</ref> and Alzheimer's disease.<ref name="pmid18088381">{{cite journal | vauthors = Hooper C, Killick R, Lovestone S | title = The GSK3 hypothesis of Alzheimer's disease | journal = Journal of Neurochemistry | volume = 104 | issue = 6 | pages = 1433–1439 | date = March 2008 | pmid = 18088381 | pmc = 3073119 | doi = 10.1111/j.1471-4159.2007.05194.x }}</ref> It is active in resting cells and is inhibited by several hormones such as [[insulin]], [[endothelial growth factor]], and [[platelet-derived growth factor]]. Insulin indirectly inactivates GSK3 via downstream phosphorylation of the specific serine residues Ser21 and Ser9 in GSK-3 isoforms α and β, respectively via the [[PI3K/Akt pathway]].<ref name="hermida-kumar-2017">{{cite journal |last1=Hermida |first1=Miguel A. |last2=Kumar |first2=J. Dinesh |last3=Leslie |first3=Nick R. |title=GSK3 and its interactions with the PI3K/AKT/mTOR signalling network |journal=Advances in Biological Regulation |date=August 2017 |volume=65 |pages=5–15 |doi=10.1016/j.jbior.2017.06.003 |pmid=28712664 |url=https://pubmed.ncbi.nlm.nih.gov/28712664/ |access-date=15 December 2023}}</ref><ref name="insulin-akt-pp1-2019">{{cite journal |last1=Li |first1=Qiqi |last2=Zhao |first2=Qiuye |last3=Zhang |first3=Junyu |last4=Linkang |first4=Linkang |last5=Wenhao |first5=Wenhao |last6=Chua |first6=BoonTin |last7=Chen |first7=Yan |last8=Xu |first8=Li |last9=Li |first9=Peng |title=The Protein Phosphatase 1 Complex Is a Direct Target of AKT that Links Insulin Signaling to Hepatic Glycogen Deposition |journal=Cell Reports |date=September 24, 2019|volume=28 |issue=13 |pages=3406–3422 |doi=10.1016/j.celrep.2019.08.066 |pmid=31553910 |doi-access=free }}</ref>

{{As of|2019}}, GSK-3 is the only type of '''glycogen synthase kinase''' named and recognized. The [[gene symbol]]s for GSK1 and GSK2 have been withdrawn by the [[HUGO Gene Nomenclature Committee]] (HGNC), and no new names for these "genes" nor their locations have been specified.<ref>{{MeshName|Glycogen+synthase+kinase}}</ref><ref>[https://www.ncbi.nlm.nih.gov/gene/2929 GSK1], [https://www.ncbi.nlm.nih.gov/gene/2930 GSK2]. ''NCBI Gene''.</ref>

==Mechanism==
[[File:GSK3 active site.png|thumb|left|alt=Active site of GSK-3|The active site of GSK-3. The three residues in blue bind the priming phosphate on the substrate, as demonstrated by the ligand. Residues D181, D200, K85, and E97.]]

GSK-3 functions by [[phosphorylation|phosphorylating]] a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).<ref name="pmid11440715">{{cite journal | vauthors = Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH | title = Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition | journal = Cell | volume = 105 | issue = 6 | pages = 721–732 | date = June 2001 | pmid = 11440715 | doi = 10.1016/S0092-8674(01)00374-9 | s2cid = 17401752 | doi-access = free }}</ref>

==Glycogen synthase==
'''[[Glycogen synthase]]''' is an [[enzyme]] that is responsible in [[glycogen]] synthesis. It is activated by [[glucose 6-phosphate]] (G6P), and inhibited by [[glycogen synthase kinase]]s ([[GSK3]]). Those two mechanisms play an important role in glycogen metabolism.<ref>{{cite journal | vauthors = Bouskila M, Hunter RW, Ibrahim AF, Delattre L, Peggie M, van Diepen JA, Voshol PJ, Jensen J, Sakamoto K | display-authors = 6 | title = Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle | journal = Cell Metabolism | volume = 12 | issue = 5 | pages = 456–466 | date = November 2010 | pmid = 21035757 | doi = 10.1016/j.cmet.2010.10.006 | doi-access = free }}</ref>

== Function ==
Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target.<ref name="pmid7803763">{{cite journal | vauthors = Woodgett JR | title = Regulation and functions of the glycogen synthase kinase-3 subfamily | journal = Seminars in Cancer Biology | volume = 5 | issue = 4 | pages = 269–275 | date = August 1994 | pmid = 7803763 }}</ref><ref name="pmid11579232">{{cite journal | vauthors = Woodgett JR | title = Judging a protein by more than its name: GSK-3 | journal = Science's STKE | volume = 2001 | issue = 100 | pages = re12 | date = September 2001 | pmid = 11579232 | doi = 10.1126/stke.2001.100.re12 | s2cid = 19052833 }}</ref><ref name="pmid11749387">{{cite journal | vauthors = Ali A, Hoeflich KP, Woodgett JR | title = Glycogen synthase kinase-3: properties, functions, and regulation | journal = Chemical Reviews | volume = 101 | issue = 8 | pages = 2527–2540 | date = August 2001 | pmid = 11749387 | doi = 10.1021/cr000110o | s2cid = 12925005 }}</ref>  GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis.

GSK-3 was originally discovered in the context of its involvement in regulating [[glycogen synthase]].<ref name="pmid6249596"/> After being primed by [[casein kinase 2]] (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity.<ref name="pmid19366350">{{cite journal | vauthors = Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A | title = Glycogen synthase kinase 3: more than a namesake | journal = British Journal of Pharmacology | volume = 156 | issue = 6 | pages = 885–898 | date = March 2009 | pmid = 19366350 | pmc = 2697722 | doi = 10.1111/j.1476-5381.2008.00085.x }}</ref> In addition to its role in regulating glycogen synthase, GSK-3 has been implicated in other aspects of glucose homeostasis, including the phosphorylation of insulin receptor [[IRS1]]<ref name="pmid15574412">{{cite journal | vauthors = Liberman Z, Eldar-Finkelman H | title = Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling | journal = The Journal of Biological Chemistry | volume = 280 | issue = 6 | pages = 4422–4428 | date = February 2005 | pmid = 15574412 | doi = 10.1074/jbc.M410610200 | doi-access = free }}</ref> and of the gluconeogenic enzymes [[phosphoenolpyruvate carboxykinase]] and [[glucose 6 phosphatase]].<ref name="pmid11334436">{{cite journal | vauthors = Lochhead PA, Coghlan M, Rice SQ, Sutherland C | title = Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression | journal = Diabetes | volume = 50 | issue = 5 | pages = 937–946 | date = May 2001 | pmid = 11334436 | doi = 10.2337/diabetes.50.5.937 | doi-access = free }}</ref> However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3.<ref name="pmid19366350"/>

GSK-3 has also been shown to regulate immune and migratory processes. GSK-3 participates in a number of signaling pathways in the innate immune response, including pro-inflammatory cytokine and interleukin production.<ref name="pmid16944320">{{cite journal | vauthors = Jope RS, Yuskaitis CJ, Beurel E | title = Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics | journal = Neurochemical Research | volume = 32 | issue = 4–5 | pages = 577–595 | date = Apr–May 2007 | pmid = 16944320 | pmc = 1970866 | doi = 10.1007/s11064-006-9128-5 }}</ref><ref name="pmid21095632">{{cite journal | vauthors = Wang H, Brown J, Martin M | title = Glycogen synthase kinase 3: a point of convergence for the host inflammatory response | journal = Cytokine | volume = 53 | issue = 2 | pages = 130–140 | date = February 2011 | pmid = 21095632 | pmc = 3021641 | doi = 10.1016/j.cyto.2010.10.009 }}</ref> The inactivation of [[GSK3B]] by various protein kinases also affects the adaptive immune response by inducing cytokine production and proliferation in naïve and memory CD4+ T cells.<ref name="pmid21095632"/> In cellular migration, an integral aspect of inflammatory responses, the inhibition of GSK-3 has been reported to play conflicting roles, as local inhibition at growth cones has been shown to promote motility while global inhibition of cellular GSK-3 has been shown to inhibit cell spreading and migration.<ref name="pmid16944320"/>

GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate [[Beta-catenin]], thus targeting it for degradation.<ref name="pmid22275880">{{cite journal | vauthors = Mills CN, Nowsheen S, Bonner JA, Yang ES | title = Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors | journal = Frontiers in Molecular Neuroscience | volume = 4 | pages = 47 | year = 2011 | pmid = 22275880 | pmc = 3223722 | doi = 10.3389/fnmol.2011.00047 | doi-access = free }}</ref> GSK-3 is therefore a part of the canonical [[Beta-catenin]]/[[Wnt signaling pathway|Wnt]] pathway, which signals the cell to divide and proliferate. GSK-3 phosphorylates cyclins D and E, which are important for the transition from G1 to S phase, and causes their degradation. The transcription factors c-myc and c-fos (also S phase promoters ), which are primarily phosphorylated by the dual-specificity tyrosine phosphorylation-regulated kinase, are also phosphorylated by GSK3, causing them to be degraded.<ref name="Glibo_2021">{{cite journal | vauthors = Glibo M, Serman A, Karin-Kujundzic V, Bekavac Vlatkovic I, Miskovic B, Vranic S, Serman L | title = The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review | journal = Bosnian Journal of Basic Medical Sciences | volume = 21 | issue = 1 | pages = 5–18 | date = February 2021 | pmid = 32767962 | pmc = 7861620 | doi = 10.17305/bjbms.2020.5036 }}</ref> GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate [[apoptosis]].<ref name="pmid15102436"/> GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as [[p53]]<ref name="pmid12048243">{{cite journal | vauthors = Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS | display-authors = 6 | title = Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 7951–7955 | date = June 2002 | pmid = 12048243 | pmc = 123001 | doi = 10.1073/pnas.122062299 | doi-access = free | bibcode = 2002PNAS...99.7951W }}</ref> and inactivating survival-promoting factors through phosphorylation.<ref name="pmid11579131">{{cite journal | vauthors = Grimes CA, Jope RS | title = CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium | journal = Journal of Neurochemistry | volume = 78 | issue = 6 | pages = 1219–1232 | date = September 2001 | pmid = 11579131 | pmc = 1947002 | doi = 10.1046/j.1471-4159.2001.00495.x }}</ref> The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3β knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis.<ref name="pmid18701488">{{cite journal | vauthors = Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W, Bailey R, Maric D, Zenklusen JC, Lee J, Fine HA | display-authors = 6 | title = Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation | journal = Cancer Research | volume = 68 | issue = 16 | pages = 6643–6651 | date = August 2008 | pmid = 18701488 | pmc = 2585745 | doi = 10.1158/0008-5472.CAN-08-0850 }}</ref> Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.<ref name="pmid22675363">{{cite journal | vauthors = Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE, Thotala D | title = GSK-3β: A Bifunctional Role in Cell Death Pathways | journal = International Journal of Cell Biology | volume = 2012 | pages = 930710 | date = May 2012 | pmid = 22675363 | pmc = 3364548 | doi = 10.1155/2012/930710 | doi-access = free }}</ref>

GSK-3 is also involved in nuclear transcriptional activator kappa B (NFκB) signaling pathway, Hedgehog signaling pathway, Notch signaling pathway, and epithelial-mesenchymal transition.<ref name="Glibo_2021" />

Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation and is considered an "Ace" among kinases.<ref>{{cite journal |last1=Mathuram |first1=TL |title=GSK-3: An "Ace" Among Kinases. |journal=Cancer Biotherapy & Radiopharmaceuticals |date=15 May 2024 |volume=39 |issue=9 |pages=619–631 |doi=10.1089/cbr.2024.0025 |pmid=38746994}}</ref>

The speed and efficacy of GSK-3 phosphorylation is regulated by several factors. Phosphorylation of certain GSK-3 residues can increase or decrease its ability to bind substrate. Phosphorylation at tyrosine-216 in GSK-3β or tyrosine-279 in GSK-3α enhances the enzymatic activity of GSK-3, while phosphorylation of autoinhibitory serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see figure).<ref name="pmid16944320"/> Further, GSK-3 is unusual among kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate. A phosphorylated serine or threonine residue located four amino acids C-terminal to the target site of phosphorylation allows the substrate to bind a pocket of positive charge formed by arginine and lysine residues.<ref name="pmid19366350"/><ref name="pmid12615961">{{cite journal | vauthors = Doble BW, Woodgett JR | title = GSK-3: tricks of the trade for a multi-tasking kinase | journal = Journal of Cell Science | volume = 116 | issue = Pt 7 | pages = 1175–1186 | date = April 2003 | pmid = 12615961 | pmc = 3006448 | doi = 10.1242/jcs.00384 }}</ref>

Depending on the pathway in which it is being utilized, GSK-3 may be further regulated by cellular localization or the formation of protein complexes. The activity of GSK-3 is far greater in the nucleus and mitochondria than in the cytosol in cortical neurons,<ref name="pmid14663202">{{cite journal | vauthors = Bijur GN, Jope RS | title = Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria | journal = NeuroReport | volume = 14 | issue = 18 | pages = 2415–2419 | date = December 2003 | pmid = 14663202 | doi = 10.1097/00001756-200312190-00025 | s2cid = 43633965 }}</ref> while the phosphorylation of Beta-catenin by GSK-3 is mediated by the binding of both proteins to [[Axin]], a scaffold protein, allowing Beta-catenin to access the active site of GSK-3.<ref name="pmid16944320"/> 

Insulin indirectly inactivates GSK3 via downstream phosphorylation of the specific serine residues Ser21 and Ser9 in GSK-3 isoforms α and β, respectively, via the [[PI3K/Akt pathway]] (protein kinase B).<ref name="hermida-kumar-2017" /><ref name="insulin-akt-pp1-2019" />

==Disease relevance==

Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in [[Alzheimer's disease]], [[type 2 diabetes mellitus]] (T2DM), some forms of [[cancer]], and [[bipolar disorder]].<ref name="Saraswati_2017">{{cite journal | vauthors = Saraswati AP, Ali Hussaini SM, Krishna NH, Babu BN, Kamal A | title = Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions | journal = European Journal of Medicinal Chemistry | volume = 144 | pages = 843–858 | date = January 2018 | pmid = 29306837 | doi = 10.1016/j.ejmech.2017.11.103 }}</ref>

There is evidence that [[Lithium (medication)|lithium]], which is used as a treatment for [[bipolar disorder]], acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition may stabilize mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect.<ref name="pmid16944320"/> Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.<ref>{{cite journal | vauthors = Yin L, Wang J, Klein PS, Lazar MA | title = Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock | journal = Science | volume = 311 | issue = 5763 | pages = 1002–1005 | date = February 2006 | pmid = 16484495 | doi = 10.1126/science.1121613 | s2cid = 11240826 | bibcode = 2006Sci...311.1002Y }}</ref> Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.<ref>{{cite journal | vauthors = Rybakowski JK, Dmitrzak-Weglarz M, Dembinska-Krajewska D, Hauser J, Akiskal KK, Akiskal HH | title = Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder | journal = Journal of Affective Disorders | volume = 159 | pages = 80–84 | date = April 2014 | pmid = 24679394 | doi = 10.1016/j.jad.2014.02.024 }}</ref>

GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of [[Beta amyloid|amyloid-β]] (Aβ) deposits and the formation of [[neurofibrillary tangle]]s. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the [[hyperphosphorylation]] of [[tau protein]]s, which leads to the tangles.<ref name="pmid15102436"/><ref name="pmid16944320"/> Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.<ref name="pmid19038340">{{cite journal | vauthors = Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P, Ma Q, Cole GM, Frautschy SA | display-authors = 6 | title = GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals | journal = Neurobiology of Disease | volume = 33 | issue = 2 | pages = 193–206 | date = February 2009 | pmid = 19038340 | pmc = 4313761 | doi = 10.1016/j.nbd.2008.10.007 }}</ref>

In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote [[apoptosis]] in some cases, it has also been reported to be a key factor in [[tumorigenesis]] in some cancers.<ref name="Wang2008">{{cite journal | vauthors = Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML | title = Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy | journal = Nature | volume = 455 | issue = 7217 | pages = 1205–1209 | date = October 2008 | pmid = 18806775 | pmc = 4084721 | doi = 10.1038/nature07284 | bibcode = 2008Natur.455.1205W }}</ref> Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.<ref name="pmid18701488"/><ref name="pmid22201186">{{cite journal | vauthors = Marchand B, Tremblay I, Cagnol S, Boucher MJ | title = Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms | journal = Carcinogenesis | volume = 33 | issue = 3 | pages = 529–537 | date = March 2012 | pmid = 22201186 | doi = 10.1093/carcin/bgr309 | doi-access = free }}</ref> GSK-3 also seems to be responsible for NFκB aberrant activity in pediatric acute lymphoblastic leukemia and pancreatic cancer cells. In renal cancer cells, GSK-3 inhibitors induce cell cycle arrest, differentiation of the malignant cells, and autophagy. In contrast to the above neoplasms, high expression of inactive pGSK3β-S9 is found in skin, oral, and lung cancers, suggesting tumor suppressive effects of the enzyme in these cancers. In melanoma, the microRNA miR-769 inhibits GSK-3 activity during the tumor development process, also indicating tumor suppressive effects of GSK3.<ref name="Glibo_2021" />

GSK-3 inhibitors have also shown promise in the treatment of T2DM.<ref name="pmid19366350"/> Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice.<ref name="pmid16944320"/> GSK-3 inhibitors may also have therapeutic effects on [[hemorrhagic transformation]] after acute ischemic stroke.<ref name="pmid26671619">{{cite journal | vauthors = Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J | display-authors = 6 | title = GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats | journal = Molecular Neurobiology | volume = 53 | issue = 10 | pages = 7028–7036 | date = December 2016 | pmid = 26671619 | pmc = 4909586 | doi = 10.1007/s12035-015-9607-2 }}</ref> GSK-3 can negatively regulate the insulin signaling pathway by inhibiting IRS1 via phosphorylation of serine-332,<ref name="pmid15574412" /> rendering the insulin receptor incapable of activating IRS1 and further initiating the canonical PI3K/Akt pathway. The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.

GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells.<ref>{{cite journal | vauthors = Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE | title = Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses | journal = Immunity | volume = 44 | issue = 2 | pages = 274–286 | date = February 2016 | pmid = 26885856 | pmc = 4760122 | doi = 10.1016/j.immuni.2016.01.018 }}</ref>  GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.

== Inhibitors ==
Glycogen synthase kinase inhibitors are different [[chemotype]]s and have variable mechanisms of action; they may be [[cation]]s, from natural sources, synthetic ATP and non-ATP competitive inhibitors and substrate-competitive inhibitors. GSK3 is a bi-lobar architecture with [[N-terminal]] and [[C-terminal]], the N-terminal is responsible for ATP binding and C-terminal which is called as [[activation loop]] mediates the kinase activity, Tyrosine located at the C-terminal it essential for full GSK3 activity.<ref name=pmid16452634>{{cite journal | vauthors = Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH | title = GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction | journal = Molecular Biology of the Cell | volume = 17 | issue = 4 | pages = 1834–1844 | date = April 2006 | pmid = 16452634 | pmc = 1415316 | doi = 10.1091/mbc.E05-07-0688 }}</ref>

===Benefits of GSK-3β inhibitors===
In diabetes, GSK-3β inhibitors increase insulin sensitivity, glycogen synthesis, and glucose metabolism in skeletal muscles, and reduce obesity by affecting the [[adipogenesis]] process.<ref name="pmid23784744" /> GSK-3β is also over expressed in several types of cancers, like [[colorectal cancer|colorectal]], [[Ovarian cancer|ovarian]], and [[prostate cancer]].<ref name=pmid16452634/> GSK-3β inhibitors also aid in the treatment of [[Alzheimer's disease]],{{Citation needed|date=August 2019}} [[stroke]],<ref name="pmid26671619">{{cite journal | vauthors = Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J | display-authors = 6 | title = GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats | journal = Molecular Neurobiology | volume = 53 | issue = 10 | pages = 7028–7036 | date = December 2016 | pmid = 26671619 | pmc = 4909586 | doi = 10.1007/s12035-015-9607-2 }}</ref> and [[mood disorder]]s, including [[bipolar disorder]].<ref name="pmid18295757">{{cite journal | vauthors = Mohammad MK, Al-Masri IM, Taha MO, Al-Ghussein MA, Alkhatib HS, Najjar S, Bustanji Y | title = Olanzapine inhibits glycogen synthase kinase-3beta: an investigation by docking simulation and experimental validation | journal = European Journal of Pharmacology | volume = 584 | issue = 1 | pages = 185–191 | date = April 2008 | pmid = 18295757 | doi = 10.1016/j.ejphar.2008.01.019 }}</ref> ''In vitro'' studies have shown the beneficial effects of GSK-3 inhibitors in lung cancer,<ref>{{Cite journal |last1=Mathuram |first1=Theodore Lemuel |last2=Venkatesan |first2=Thiagarajan |last3=Das |first3=Jayanta |last4=Natarajan |first4=Umamaheswari |last5=Rathinavelu |first5=Appu |date=August 2020 |title=The apoptotic effect of GSK-3 inhibitors: BIO and CHIR 98014 on H1975 lung cancer cells through ROS generation and mitochondrial dysfunction |url=http://link.springer.com/10.1007/s10529-020-02861-w |journal=Biotechnology Letters |language=en |volume=42 |issue=8 |pages=1351–1368 |doi=10.1007/s10529-020-02861-w |pmid=32236757 |issn=0141-5492}}</ref> ovarian cancer<ref>{{Cite journal |last1=Mathuram |first1=Theodore Lemuel |last2=Ravikumar |first2=Vilwanathan |last3=Reece |first3=Lisa M. |last4=Sasikumar |first4=Changam Sheela |last5=Cherian |first5=Kotturathu Mammen |date=2017 |title=Correlative Studies Unravelling the Possible Mechanism of Cell Death in Tideglusib-Treated Human Ovarian Teratocarcinoma-Derived PA-1 Cells |url=http://www.dl.begellhouse.com/journals/0ff459a57a4c08d0,1b80d9046bc9fa9c,5dda311a012b39ce.html |journal=Journal of Environmental Pathology, Toxicology and Oncology |language=en |volume=36 |issue=4 |pages=321–344 |doi=10.1615/JEnvironPatholToxicolOncol.2017025018 |issn=0731-8898|url-access=subscription }}</ref> and neuroblastoma.<ref>{{Cite journal |last1=Mathuram |first1=Theodore Lemuel |last2=Ravikumar |first2=Vilwanathan |last3=Reece |first3=Lisa M. |last4=Karthik |first4=Selvaraju |last5=Sasikumar |first5=Changam Sheela |last6=Cherian |first6=Kotturathu Mammen |date=September 2016 |title=Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G 0 /G 1 accumulation and ROS generation |url=https://linkinghub.elsevier.com/retrieve/pii/S1382668916301910 |journal=Environmental Toxicology and Pharmacology |language=en |volume=46 |pages=194–205 |doi=10.1016/j.etap.2016.07.013|pmid=27490211 |url-access=subscription }}</ref>

===Specific agents===
Inhibitors of GSK-3 include:<ref name="pmid31553649">{{cite journal | vauthors = Noori MS, Bhatt PM, Courreges MC, Ghazanfari D, Cuckler C, Orac CM, McMills MC, Schwartz FL, Deosarkar SP, Bergmeier SC, McCall KD, Goetz DJ | display-authors = 6 | title = Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3 | journal = American Journal of Physiology. Cell Physiology | volume = 317 | issue = 6 | pages = C1289–C1303 | date = December 2019 | pmid = 31553649 | pmc = 6962522 | doi = 10.1152/ajpcell.00061.2019 }}</ref><ref name="pmid27902447">{{cite journal | vauthors = Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, Eldar-Finkelman H | title = A unique type of GSK-3 inhibitor brings new opportunities to the clinic | journal = Science Signaling | volume = 9 | issue = 454 | pages = ra110 | date = November 2016 | pmid = 27902447 | doi = 10.1126/scisignal.aah7102 | s2cid = 34207388 }}</ref><ref name="pmid22065134">{{cite journal | vauthors = Eldar-Finkelman H, Martinez A | title = GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS | journal = Frontiers in Molecular Neuroscience | volume = 4 | pages = 32 | year = 2011 | pmid = 22065134 | pmc = 3204427 | doi = 10.3389/fnmol.2011.00032 | doi-access = free }}</ref><ref name="pmid24931005">{{cite journal | vauthors = McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL, Montalto G, D'Assoro AB, Libra M, Nicoletti F, Maestro R, Basecke J, Rakus D, Gizak A, Demidenko ZN, Cocco L, Martelli AM, Cervello M | display-authors = 6 | title = GSK-3 as potential target for therapeutic intervention in cancer | journal = Oncotarget | volume = 5 | issue = 10 | pages = 2881–2911 | date = May 2014 | pmid = 24931005 | pmc = 4102778 | doi = 10.18632/oncotarget.2037 }}</ref>
{{div col|colwidth=22em}}

===Metal cations===
* [[Beryllium]]
* [[Copper]]
* [[Lithium]] ([[IC50|IC<sub>50</sub>]]=2mM)
* [[Mercury (element)|Mercury]]
* [[Tungsten]] (Indirect)
* [[Zinc]] ([[IC50|IC<sub>50</sub>]]=15μM)

===ATP-competitive===

====Marine organism-derived====
* [[6-BIO]] (IC<sub>50</sub>=1.5μM)
* [[Dibromocantharelline]] (IC<sub>50</sub>=3μM)
* [[Hymenialdesine]] (IC<sub>50</sub>=10nM)
* [[Indirubin]] (IC<sub>50</sub>=5-50nM)
* [[Meridianin]]

====Aminopyrimidines====
* [[CHIR99021]] (IC<sub>50</sub>=6.9nM-10nM)
* [[CHIR98014]] (IC<sub>50</sub>=0.58-0.65nM)
* [[CT98014]]
* [[CT98023]]
* [[CT99021]]
* [[TWS119]] (IC<sub>50</sub>=30nM)

====Arylindolemaleimide====
* [[SB-216763]] (IC<sub>50</sub>=34nM)
* [[SB-41528]] (IC<sub>50</sub>=31-78nM)

====Thiazoles====
* [[AR-A014418]] (IC<sub>50</sub>=104nM)
* [[AZD-1080]] (IC<sub>50</sub>=6.9nM-31nM)

====Paullones====
IC<sub>50</sub>=4-80nM:
* [[Alsterpaullone]]
* [[Cazpaullone]]
* [[Kenpaullone]]

====Aloisines====
IC<sub>50</sub>=0.5-1.5μM:

===Non-ATP competitive===

====Marine organism-derived====
* [[Manzamine A]] (IC<sub>50</sub>=1.5μM)
* [[Palinurine]] (IC<sub>50</sub>=4.5μM)
* [[Tricantine]] (IC<sub>50</sub>=7.5μM)

====Thiazolidinediones====
* [[TDZD-8]] (IC<sub>50</sub>=2μM)
* [[NP00111]] (IC<sub>50</sub>=2μM)
* [[NP031115]] (IC<sub>50</sub>=4μM)
* [[Tideglusib]] (IC<sub>50</sub>=60nM)

====Halomethylketones====
* [[HMK-32]] (IC<sub>50</sub>=1.5μM)

====Peptides====
* [[L803-mts]] (IC<sub>50</sub>=20μM)
* [[L807-mts]] (IC<sub>50</sub>=1μM)

====Unknown Mechanism (small-molecule inhibitors)====
* [[COB-187]] (IC<sub>50</sub>=11nM-22nM)
* [[COB-152]] (IC<sub>50</sub>=77nM-132nM)
{{div col end}}

===Lithium===
Lithium which is used in the treatment of [[bipolar disorder]] was the first natural GSK-3 inhibitor discovered. It inhibits GSK-3 directly by competition with magnesium ions and indirectly by phosphorylation and auto-regulation of serine.
Lithium has been found to have insulin-like effects on glucose metabolism, including stimulation of glycogen synthesis in fat cells, skin, and muscles, increasing glucose uptake, and activation of GS activity. In addition to inhibition of GSK-3, it also inhibits other enzymes involved in the regulation of glucose metabolisms, such as myo-inositol-1-monophosphatase and 1,6 bisphosphatase. Also, it has shown therapeutic benefit in Alzheimer's and other neurodegenerative diseases such as epileptic neurodegeneration.<ref name="pmid22065134" />

===Naproxen and Cromolyn===
Naproxen is a [[Nonsteroidal anti-inflammatory drug|non-steroidal anti-inflammatory drug]] while cromolyn is an [[anti-allergic agent]] which acts as a [[mast cell]] stabilizer. Both drugs have demonstrated the anticancer effect in addition to hypoglycemic effect due to inhibition of glycogen synthase kinase-3β (GSK-3β).

To validate the anti-GSK-3β hypothesis of naproxen and cromolyn, docking of the two structures against GSK-3β binding pocket and comparing their fitting with known GSK-3β inhibitor ARA014418 was performed, in addition to measuring the serum glucose, serum insulin, serum C-peptide, weight variation and hepatic glycogen levels for normal and diabetic fasting animal's models to assess their in vitro hypoglycemic effects.{{Citation needed|date=August 2019}}

Naproxen and cromolyn were successfully docked into the binding site of GSK-3β (both were fitted into its binding pocket). They exhibited electrostatic, hydrophobic, and hydrogen-bonding interactions with key amino acids within the [[binding pocket]] with binding interaction profiles similar to AR-A014418 (the known inhibitor). The negative charges of the carboxylic acid groups in both drugs interact electrostatically with the positively charged guanidine group of Arg141. Moreover, the hydrogen bonding interactions between carboxylic acid moieties of cromolyn and the ammonium groups of Lys183 and Lys60, in addition to π-stacking of the naphthalene ring system of naproxen with the phenolic ring of Tyr134.

Antidiabetic effects of naproxen and cromolyn: In normal animal models, both drugs have shown dose-dependent reduction in blood glucose levels and rise in glycogen levels. In chronic type II diabetic model, glucose levels were also reduced, and glycogen level and insulin levels were elevated in a dose-dependent manner with a reduction in plasma glucose.{{Citation needed|date=August 2019}}

Anti-obesity effects of naproxen and cromolyn: Both drugs showed significant anti-obesity effects as they reduce body weight, resistin, and glucose levels in a dose-dependent manner. They were also found to elevate [[adiponectin]], insulin, and C-peptide levels in a dose-dependent manner.<ref name=pmid23784744>{{cite journal | vauthors = Motawi TM, Bustanji Y, El-Maraghy SA, Taha MO, Al Ghussein MA | title = Naproxen and cromolyn as new glycogen synthase kinase 3β inhibitors for amelioration of diabetes and obesity: an investigation by docking simulation and subsequent in vitro/in vivo biochemical evaluation | journal = Journal of Biochemical and Molecular Toxicology | volume = 27 | issue = 9 | pages = 425–436 | date = September 2013 | pmid = 23784744 | doi = 10.1002/jbt.21503 | s2cid = 46597394 }}</ref>

===Famotidine===
Famotidine is a specific, long-acting [[H2 antagonist]] that decreases gastric acid secretion. It is used in the treatment of peptic ulcer disease, GERD, and pathological hypersecretory conditions, like Zollinger–Ellison syndrome. (14,15) H2-receptor antagonists affect hormone metabolism, but their effect on glucose metabolism is not well established. (16) A study has revealed a glucose-lowering effect for famotidine.{{cn|date=April 2023}}

The study of famotidine binding to the enzyme has showed that famotidine can be docked within the binding pocket of GSK-3β making significant interactions with key points within the GSK-3β binding pocket. Strong hydrogen bond interactions with the key amino acids PRO-136 and VAL -135 and potential hydrophobic interaction with LEU-188 were similar to those found in the ligand binding to the enzyme (AR-A014418).{{citation needed|date=February 2019}}

Furthermore, famotidine showed high GSK-3β binding affinity and inhibitory activity due to interactions that stabilize the complex, namely hydrogen bonding of guanidine group in famotidine with the sulfahydryl moiety in CYS-199; and electrostatic interactions between the same guanidine group with the carboxyl group in ASP-200, the hydrogen bond  between the terminal NH2 group, the OH of the TYR-143, and the hydrophobic interaction of the sulfur atom in the thioether with ILE-62. In vitro studies showed that famotidine inhibits GSK-3β activity and increases liver glycogen reserves in a dose dependent manner. A fourfold increase in the liver glycogen level with the use of the highest dose of famotidine (4.4&nbsp;mg/kg) was observed. Also, famotidine has been shown to decrease serum glucose levels 30, and 60 minutes after oral glucose load in healthy individuals. As a GSK-3β inhibitor, the IC<sub>50</sub> value of famotidine is 1.44μM.<ref>{{cite journal | vauthors = Mohammad M, Al-Masri IM, Issa A, Al-Ghussein MA, Fararjeh M, Alkhatib H, Taha MO, Bustanji Y | display-authors = 6 | title = Famotidine inhibits glycogen synthase kinase-3β: an investigation by docking simulation and experimental validation | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 28 | issue = 4 | pages = 690–694 | date = August 2013 | pmid = 22512725 | doi = 10.3109/14756366.2012.672413 | s2cid = 11890710 | doi-access = free }}</ref>

===Curcumin===
Curcumin, which Is a constituent of [[turmeric]] spice, has flavoring and coloring properties.<ref>{{cite journal | vauthors = Maheshwari RK, Singh AK, Gaddipati J, Srimal RC | title = Multiple biological activities of curcumin: a short review | journal = Life Sciences | volume = 78 | issue = 18 | pages = 2081–2087 | date = March 2006 | pmid = 16413584 | doi = 10.1016/j.lfs.2005.12.007 }}</ref> It has two symmetrical forms: enol (the most abundant forms) and ketone.<ref>{{cite journal | vauthors = Balasubramanian K | title = Molecular orbital basis for yellow curry spice curcumin's prevention of Alzheimer's disease | journal = Journal of Agricultural and Food Chemistry | volume = 54 | issue = 10 | pages = 3512–3520 | date = May 2006 | pmid = 19127718 | doi = 10.1021/jf0603533 | bibcode = 2006JAFC...54.3512B }}</ref><ref>{{cite journal | vauthors = Payton F, Sandusky P, Alworth WL | title = NMR study of the solution structure of curcumin | journal = Journal of Natural Products | volume = 70 | issue = 2 | pages = 143–146 | date = February 2007 | pmid = 17315954 | doi = 10.1021/np060263s | bibcode = 2007JNAtP..70..143P }}</ref>

Curcumin has wide pharmacological activities: anti-inflammatory,<ref>{{cite journal | vauthors = Kohli K, Ali J, Ansari MJ, Raheman Z |doi=10.4103/0253-7613.16209 |title=Curcumin: A natural antiinflammatory agent |journal=Indian Journal of Pharmacology |volume=37 |issue=3 |pages=141 |year=2005 |url=http://www.bioline.org.br/pdf?ph05037 |doi-access=free |hdl=1807/8668 |hdl-access=free }}</ref> anti-microbial,<ref>{{cite journal | vauthors = Negi PS, Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK | title = Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture | journal = Journal of Agricultural and Food Chemistry | volume = 47 | issue = 10 | pages = 4297–4300 | date = October 1999 | pmid = 10552805 | doi = 10.1021/jf990308d | bibcode = 1999JAFC...47.4297N }}</ref> hypoglycemic, anti-oxidant, and wound healing effects.<ref>{{cite journal | vauthors = Sidhu GS, Singh AK, Thaloor D, Banaudha KK, Patnaik GK, Srimal RC, Maheshwari RK | title = Enhancement of wound healing by curcumin in animals | journal = Wound Repair and Regeneration | volume = 6 | issue = 2 | pages = 167–177 | year = 1998 | pmid = 9776860 | doi = 10.1046/j.1524-475X.1998.60211.x | s2cid = 21440334 }}</ref> In animal models with Alzheimer disease, it has anti-destructive effect of beta amyloid in the brain,<ref>{{cite journal | vauthors = Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM | display-authors = 6 | title = Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo | journal = The Journal of Biological Chemistry | volume = 280 | issue = 7 | pages = 5892–5901 | date = February 2005 | pmid = 15590663 | doi = 10.1074/jbc.M404751200 | doi-access = free }}</ref> and recently it shows anti-malarial activity.<ref>{{cite journal | vauthors = Mishra S, Karmodiya K, Surolia N, Surolia A | title = Synthesis and exploration of novel curcumin analogues as anti-malarial agents | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 6 | pages = 2894–2902 | date = March 2008 | pmid = 18194869 | doi = 10.1016/j.bmc.2007.12.054 }}</ref>

Curcumin also has chemo preventative and anti-cancer effects,{{cn|date=September 2024}} and it has been shown to attenuate oxidative stress and renal dysfunction in diabetic animals with chronic use.<ref>{{cite journal | vauthors = Sharma S, Kulkarni SK, Chopra K | title = Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats | journal = Clinical and Experimental Pharmacology & Physiology | volume = 33 | issue = 10 | pages = 940–945 | date = October 2006 | pmid = 17002671 | doi = 10.1111/j.1440-1681.2006.04468.x | s2cid = 25193929 }}</ref>

Curcumin's mechanism of action is anti-inflammatory; it inhibits the nuclear transcriptional activator kappa B ([[NF-κB|NF-KB]]) that is activated whenever there is inflammatory response.{{citation needed|date=February 2019}}

[[NF-kB]] has two regulatory factors, IkB and GSK-3,<ref>{{cite journal | vauthors = Demarchi F, Bertoli C, Sandy P, Schneider C | title = Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39583–39590 | date = October 2003 | pmid = 12871932 | doi = 10.1074/jbc.M305676200 | doi-access = free }}</ref> which suggests curcumin directly binds and inhibits GSK-3B. An in vitro study confirmed GSK-3B inhibition by simulating molecular docking using a silico docking technique.<ref name="Bustanji_2009">{{cite journal | vauthors = Bustanji Y, Taha MO, Almasri IM, Al-Ghussein MA, Mohammad MK, Alkhatib HS | title = Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 24 | issue = 3 | pages = 771–778 | date = June 2009 | pmid = 18720192 | doi = 10.1080/14756360802364377 | s2cid = 23137441 }}</ref> The concentration at which 50% of GK-3B would be inhibited by curcumin is 66.3 nM.<ref name="Bustanji_2009" />

Among its two forms, experimental and theoretical studies show that the enol form is the favored form due to its intra-molecular hydrogen bonding, and an NMR experiment show that enol form exist in a variety of solvents.{{citation needed|date=February 2019}}

===Olanzapine===
[[Antipsychotic]] medications are increasingly used for [[schizophrenia]], bipolar disorder, anxiety, and other psychiatric conditions<ref>{{cite web |publisher=Mind.org.uk |year=2018 |title=Antipsychotics A-Z |url=https://www.mind.org.uk/information-support/drugs-and-treatments/antipsychotics-a-z }}{{MEDRS|date=February 2019}}</ref> Atypical antipsychotics are more commonly used than first generation antipsychotics because they decrease the risk of extrapyramidal symptoms, such as [[tardive dyskinesia]], and have better efficacy.<ref name=WebMD>{{cite web |title=Antipsychotic Medication for Bipolar Disorder |publisher=WebMD |url=https://www.webmd.com/bipolar-disorder/guide/antipsychotic-medication }}</ref>

Olanzapine and atypical antipsychotics induce weight gain through increasing body fat.<ref>{{cite journal | vauthors = Goudie AJ, Smith JA, Halford JC | title = Characterization of olanzapine-induced weight gain in rats | journal = Journal of Psychopharmacology | volume = 16 | issue = 4 | pages = 291–296 | date = December 2002 | pmid = 12503827 | doi = 10.1177/026988110201600402 | s2cid = 23589812 }}</ref> It also affects glucose metabolism, and several studies shows that it may worsen diabetes.<ref>{{cite journal | vauthors = Di Lorenzo R, Brogli A | title = Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia | journal = Neuropsychiatric Disease and Treatment | volume = 6 | pages = 573–581 | date = September 2010 | pmid = 20856920 | pmc = 2938306 | doi = 10.2147/NDT.S5463 | doi-access = free }}</ref>

A recent study shows that olanzapine inhibits GSK3 activity, suggesting olanzapine permits glycogen synthesis.  A study of the effect of olanzapine on mouse blood glucose and glycogen levels showed a significant decrease in blood glucose level and elevation of glycogen level in mice, and the IC50% of olanzapine were 91.0&nbsp;nm, which is considered a potent inhibitor. The study also illustrates that sub-chronic use of olanzapine results in potent inhibition of GSK3.<ref name=pmid18295757/>

===Pyrimidine derivatives===
[[Pyrimidine analogue]]s are antimetabolites that interfere with nucleic acid synthesis.<ref>{{cite book |doi=10.1016/B978-0-444-59499-0.00045-3 |chapter=Cytostatic and cytotoxic drugs |title=A worldwide yearly survey of new data in adverse drug reactions and interactions |volume=34 |pages=731–747 |series=Side Effects of Drugs Annual |year=2012 | vauthors = Murphy F, Middleton M |isbn=978-0-444-59499-0 }}</ref> Some of them have been shown to fit the ATP-binding pocket of GSK-3β to lower blood glucose levels and improve some neuronal diseases.<ref>{{cite journal | vauthors = Kramer T, Schmidt B, Lo Monte F | title = Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models | journal = International Journal of Alzheimer's Disease | volume = 2012 | pages = 381029 | year = 2012 | pmid = 22888461 | pmc = 3408674 | doi = 10.1155/2012/381029 | doi-access = free }}</ref>

== See also ==
* [[Ketamine]]
* [[Tau-protein kinase]]

== References ==
{{reflist|32em}}

== External links ==
* {{MeshName|Glycogen+Synthase+Kinase+3|3=Glycogen Synthase Kinase 3}}

{{Wnt signaling pathway}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
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[[Category:Protein kinases]]
[[Category:Biology of bipolar disorder]]
[[Category:EC 2.7.11]]