{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:29:12Z","timestamp":1792906152769,"version":"4.5.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"World Premier International Research Center","award":["JP21zf0127005"],"award-info":[{"award-number":["JP21zf0127005"]}]},{"name":"JSPS KAKENHI","award":["17H06095"],"award-info":[{"award-number":["17H06095"]}]},{"name":"JSPS KAKENHI","award":["22H04918"],"award-info":[{"award-number":["22H04918"]}]},{"name":"JSPS KAKENHI","award":["22K21351"],"award-info":[{"award-number":["22K21351"]}]},{"name":"JSPS KAKENHI","award":["20H00567"],"award-info":[{"award-number":["20H00567"]}]},{"name":"JSPS KAKENHI","award":["24H00671"],"award-info":[{"award-number":["24H00671"]}]},{"name":"JSPS KAKENHI","award":["26507003"],"award-info":[{"award-number":["26507003"]}]},{"name":"JSPS KAKENHI","award":["18968064"],"award-info":[{"award-number":["18968064"]}]},{"name":"World-Leading Innovative R&D on Science and Technology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Study Objectives<\/jats:title>\n                  <jats:p>Sleep\/wakefulness is regulated by intracellular signaling pathways composed of protein kinases such as salt-inducible kinase 3 (Sik3). Sik3-deficiency in neurons decreases nonrapid eye movement (NREM) sleep time and electroencephalogram (EEG) delta power during NREM sleep, while Sik3Slp mice lacking a protein kinase A (PKA)-phosphorylation site, S551, show hypersomnia phenotype. In this study, we examined how a phosphomimetic mutation of the 221st threonine residue (T221E), which provides a partial (weak) constitutive activity of the kinase, affects sleep\/wakefulness and circadian behavior. We also examined the effect of T221E substitution on the hypersomnia phenotype of Sik3Slp mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We examined the sleep\/wake behavior of heterozygous and homozygous Sik3T221E mice and Sik3T221E;Slp mice using EEG and electromyogram recording. We also examined the circadian behavior of Sik3T221E mice using a running wheel under the light\u2013dark cycle and constant darkness.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Heterozygous and homozygous Sik3T221E mice showed normal sleep time and sleep homeostatic responses. Homozygous Sik3T221E mice exhibited a delayed onset of wakefulness at the early dark phase and longer circadian periods. Sik3T221E;Slp mice showed decreased NREM sleep time and homeostatic responses compared to Sik3Slp mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results suggest that the peak onset of wakefulness is sensitive to disturbed kinase activity of SIK3, and the relationship between phosphorylation at T221 and S551 is critical for regulating sleep need.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/sleep\/zsae279","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T18:52:09Z","timestamp":1733856729000},"source":"Crossref","is-referenced-by-count":5,"title":["Partial activation of salt-inducible kinase 3 delays the onset of wakefulness and alleviates hypersomnia due to the lack of protein kinase A-phosphorylation site"],"prefix":"10.1093","volume":"48","author":[{"given":"Shinya","family":"Nakata","sequence":"first","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Fujiyama","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9287-2011","authenticated-orcid":false,"given":"Fuyuki","family":"Asano","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruna","family":"Komiya","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Hotta-Hirashima","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Juichi","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Komine","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyo","family":"Kakizaki","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Ikkyu","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiya","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Laboratory Animal Resource Center and Transborder Medical Research Center, University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory Animal Resource Center and Transborder Medical Research Center, University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7109-1777","authenticated-orcid":false,"given":"Chika","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2787-9700","authenticated-orcid":false,"given":"Hiromasa","family":"Funato","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]},{"name":"Department of Anatomy, Graduate School of Medicine, Toho University , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7358-4022","authenticated-orcid":false,"given":"Masashi","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]},{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center , Dallas, TX ,","place":["USA"]},{"name":"Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba , Tsukuba, Ibaraki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"2025021005521646300_CIT0001","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.conb.2021.08.004","article-title":"Non-REM and REM\/paradoxical sleep dynamics across phylogeny","volume":"71","author":"Jaggard","year":"2021","journal-title":"Curr Opin Neurobiol."},{"key":"2025021005521646300_CIT0002","doi-asserted-by":"publisher","first-page":"567618","DOI":"10.3389\/fpsyg.2020.567618","article-title":"Evolutionary origin of distinct NREM and REM sleep","volume":"11","author":"Yamazaki","year":"2020","journal-title":"Front Psychol."},{"issue":"0","key":"2025021005521646300_CIT0003","doi-asserted-by":"publisher","first-page":"5500","DOI":"10.1016\/j.cell.2023.10.025","article-title":"Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals","volume":"186","author":"Sang","year":"2023","journal-title":"Cell."},{"issue":"6567","key":"2025021005521646300_CIT0004","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1126\/science.abj8188","article-title":"The translational neuroscience of sleep: a contextual framework","volume":"374","author":"Grandner","year":"2021","journal-title":"Science."},{"issue":"7629","key":"2025021005521646300_CIT0005","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/nature20142","article-title":"Forward-genetics analysis of sleep in randomly mutagenized mice","volume":"539","author":"Funato","year":"2016","journal-title":"Nature."},{"issue":"1","key":"2025021005521646300_CIT0006","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.neuron.2016.02.032","article-title":"Involvement of Ca(2+)-dependent hyperpolarization in sleep duration in mammals","volume":"90","author":"Tatsuki","year":"2016","journal-title":"Neuron."},{"key":"2025021005521646300_CIT0007","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/s41586-022-05510-6","article-title":"A signalling pathway for transcriptional regulation of sleep amount in mice","volume":"612","author":"Zhou","year":"2022","journal-title":"Nature."},{"key":"2025021005521646300_CIT0008","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/s41586-022-05450-1","article-title":"Kinase signalling in excitatory neurons regulates sleep quantity and depth","volume":"612","author":"Kim","year":"2022","journal-title":"Nature."},{"issue":"463","key":"2025021005521646300_CIT0009","doi-asserted-by":"publisher","first-page":"eaai9219","DOI":"10.1126\/scisignal.aai9219","article-title":"ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness","volume":"10","author":"Mikhail","year":"2017","journal-title":"Sci Signal"},{"issue":"3","key":"2025021005521646300_CIT0010","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1534\/genetics.120.303435","article-title":"Sleep architecture in mice is shaped by the transcription factor AP-2\u03b2","volume":"216","author":"Nakai","year":"2020","journal-title":"Genetics."},{"issue":"18","key":"2025021005521646300_CIT0011","doi-asserted-by":"publisher","first-page":"7118","DOI":"10.1073\/pnas.0602006103","article-title":"NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions","volume":"103","author":"Franken","year":"2006","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2025021005521646300_CIT0012","doi-asserted-by":"publisher","first-page":"e58331","DOI":"10.7554\/eLife.58331","article-title":"An essential role for MEF2C in the cortical response to loss of sleep in mice","volume":"9","author":"Bjorness","year":"2020","journal-title":"Elife"},{"issue":"41","key":"2025021005521646300_CIT0013","doi-asserted-by":"publisher","first-page":"10458","DOI":"10.1073\/pnas.1810823115","article-title":"A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice","volume":"115","author":"Honda","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"3","key":"2025021005521646300_CIT0014","first-page":"195","article-title":"two process model of sleep regulation","volume":"1","author":"Borb\u00e9ly","year":"1982","journal-title":"Hum Neurobiol."},{"issue":"8","key":"2025021005521646300_CIT0015","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.1523\/JNEUROSCI.21-08-02610.2001","article-title":"The homeostatic regulation of sleep need is under genetic control","volume":"21","author":"Franken","year":"2001","journal-title":"J Neurosci."},{"key":"2025021005521646300_CIT0016","doi-asserted-by":"publisher","first-page":"175877","DOI":"10.1016\/j.ejphar.2023.175877","article-title":"Face validation and pharmacologic analysis of Sik3Sleepy mutant mouse as a possible model of idiopathic hypersomnia","volume":"954","author":"Elhosainy","year":"2023","journal-title":"Eur J Pharmacol."},{"issue":"9","key":"2025021005521646300_CIT0017","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1016\/j.cellsig.2012.05.001","article-title":"cAMP-elevation mediated by \u03b2-adrenergic stimulation inhibits salt-inducible kinase (SIK) 3 activity in adipocytes","volume":"24","author":"Berggreen","year":"2012","journal-title":"Cell Signal."},{"issue":"3","key":"2025021005521646300_CIT0018","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1111\/febs.14351","article-title":"14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible kinases (SIKs)","volume":"285","author":"Sonntag","year":"2018","journal-title":"FEBS J."},{"issue":"11","key":"2025021005521646300_CIT0019","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsac198","article-title":"Regulation of sleep quantity and intensity by long and short isoforms of SLEEPY kinase","volume":"45","author":"Xu","year":"2022","journal-title":"Sleep."},{"issue":"11","key":"2025021005521646300_CIT0020","doi-asserted-by":"publisher","first-page":"e2218209120","DOI":"10.1073\/pnas.2218209120","article-title":"SIK3-HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice","volume":"120","author":"Asano","year":"2023","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"4","key":"2025021005521646300_CIT0021","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/sj.emboj.7600110","article-title":"LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK\/PAR-1","volume":"23","author":"Lizcano","year":"2004","journal-title":"EMBO J."},{"issue":"12","key":"2025021005521646300_CIT0022","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1111\/j.1742-4658.2006.05291.x","article-title":"Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade","volume":"273","author":"Katoh","year":"2006","journal-title":"FEBS J."},{"issue":"5","key":"2025021005521646300_CIT0023","doi-asserted-by":"publisher","first-page":"e37803","DOI":"10.1371\/journal.pone.0037803","article-title":"Involvement of SIK3 in glucose and lipid homeostasis in mice","volume":"7","author":"Uebi","year":"2012","journal-title":"PLoS One."},{"issue":"1","key":"2025021005521646300_CIT0024","doi-asserted-by":"publisher","first-page":"iyad136","DOI":"10.1093\/genetics\/iyad136","article-title":"Sleep need, the key regulator of sleep homeostasis, is indicated and controlled by phosphorylation of threonine 221 in salt-inducible kinase 3","volume":"225","author":"Li","year":"2023","journal-title":"Genetics."},{"key":"2025021005521646300_CIT0025","doi-asserted-by":"publisher","first-page":"739236","DOI":"10.3389\/fnins.2021.739236","article-title":"The role of reproductive hormones in sex differences in sleep homeostasis and arousal response in mice","volume":"15","author":"Choi","year":"2021","journal-title":"Front Neurosci."},{"issue":"2","key":"2025021005521646300_CIT0026","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.kint.2018.02.025","article-title":"A mutation in transcription factor MAFB causes focal segmental glomerulosclerosis with Duane retraction syndrome","volume":"94","author":"Sato","year":"2018","journal-title":"Kidney Int."},{"issue":"9","key":"2025021005521646300_CIT0027","doi-asserted-by":"publisher","first-page":"417","DOI":"10.17221\/2293-pse","article-title":"dCAPS method: advantages, troubles and solution","volume":"53","author":"Hrub\u00e1","year":"2008","journal-title":"Plant Soil Environ."},{"issue":"3","key":"2025021005521646300_CIT0028","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1042\/BJ20111932","article-title":"The AMPK-related kinase SIK2 is regulated by cAMP via phosphorylation at Ser358 in adipocytes","volume":"444","author":"Henriksson","year":"2012","journal-title":"Biochem J."},{"issue":"32","key":"2025021005521646300_CIT0029","doi-asserted-by":"publisher","first-page":"16062","DOI":"10.1073\/pnas.1906774116","article-title":"Methodology and theoretical basis of forward genetic screening for sleep\/wakefulness in mice","volume":"116","author":"Miyoshi","year":"2019","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2025021005521646300_CIT0030","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1523\/jneurosci.1004-20.2020","article-title":"Induction of mutant Sik3Sleepy allele in neurons in late infancy increases sleep need","volume":"41","author":"Iwasaki","year":"2021","journal-title":"J Neurosci."},{"issue":"4","key":"2025021005521646300_CIT0031","doi-asserted-by":"publisher","first-page":"R1127","DOI":"10.1152\/ajpregu.1998.275.4.R1127","article-title":"Genetic variation in EEG activity during sleep in inbred mice","volume":"275","author":"Franken","year":"1998","journal-title":"Am J Physiol."},{"issue":"3","key":"2025021005521646300_CIT0032","doi-asserted-by":"publisher","first-page":"589","DOI":"10.5665\/sleep.5534","article-title":"Altered sleep homeostasis in rev-erb\u03b1 knockout mice","volume":"39","author":"Mang","year":"2016","journal-title":"Sleep."},{"issue":"25","key":"2025021005521646300_CIT0033","doi-asserted-by":"publisher","first-page":"10288","DOI":"10.1073\/pnas.1308295110","article-title":"Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice","volume":"110","author":"Suzuki","year":"2013","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"2","key":"2025021005521646300_CIT0034","first-page":"155","article-title":"Genetic determinants of sleep regulation in inbred mice","volume":"22","author":"Franken","year":"1999","journal-title":"Sleep."},{"key":"2025021005521646300_CIT0035","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/S0076-6879(05)93008-5","article-title":"Methods to record circadian rhythm wheel running activity in mice","volume":"393","author":"Siepka","year":"2005","journal-title":"Methods Enzymol."},{"issue":"7","key":"2025021005521646300_CIT0036","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1042\/BCJ20200502","article-title":"Nuts and bolts of the salt-inducible kinases (SIKs)","volume":"478","author":"Darling","year":"2021","journal-title":"Biochem J."},{"issue":"7344","key":"2025021005521646300_CIT0037","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/nature10009","article-title":"Local sleep in awake rats","volume":"472","author":"Vyazovskiy","year":"2011","journal-title":"Nature."},{"key":"2025021005521646300_CIT0038","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.neures.2024.03.004","article-title":"Neuronal subtype-specific transcriptomic changes in the cerebral neocortex associated with sleep pressure","volume":"207","author":"Nakata","year":"2024","journal-title":"Neurosci Res."},{"issue":"4","key":"2025021005521646300_CIT0039","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.bbrc.2015.10.077","article-title":"DEC1 negatively regulates AMPK activity via LKB1","volume":"467","author":"Sato","year":"2015","journal-title":"Biochem Biophys Res Commun."},{"issue":"6909","key":"2025021005521646300_CIT0040","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1038\/nature01123","article-title":"Dec1 and Dec2 are regulators of the mammalian molecular clock","volume":"419","author":"Honma","year":"2002","journal-title":"Nature."}],"container-title":["SLEEP"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/sleep\/advance-article-pdf\/doi\/10.1093\/sleep\/zsae279\/60949715\/zsae279.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/48\/2\/zsae279\/60949715\/zsae279.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/48\/2\/zsae279\/60949715\/zsae279.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T05:53:07Z","timestamp":1739166787000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/sleep\/article\/doi\/10.1093\/sleep\/zsae279\/7916361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,4]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,12,4]]},"published-print":{"date-parts":[[2025,2,10]]}},"URL":"https:\/\/doi.org\/10.1093\/sleep\/zsae279","relation":{},"ISSN":["0161-8105","1550-9109"],"issn-type":[{"value":"0161-8105","type":"print"},{"value":"1550-9109","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,2]]},"published":{"date-parts":[[2024,12,4]]},"article-number":"zsae279"}}