{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T07:01:04Z","timestamp":1768114864984,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP16K08568"],"award-info":[{"award-number":["JP16K08568"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tsumura and Co","award":["JP16K08568"],"award-info":[{"award-number":["JP16K08568"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.<\/jats:p>","DOI":"10.3390\/ijms25094907","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T03:30:49Z","timestamp":1714534249000},"page":"4907","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Inhibition of TREK-1 K+ Channels via Multiple Compounds Contained in the Six Kamikihito Components, Potentially Stimulating Oxytocin Neuron Pathways"],"prefix":"10.3390","volume":"25","author":[{"given":"Kanako","family":"Miyano","sequence":"first","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Department of Dentistry, National Cancer Center Hospital, Tokyo 104-0045, Japan"},{"name":"Laboratory of Pharmacotherapeutics, Faculty of Pharmacy, Juntendo University, Chiba 279-0013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6481-0294","authenticated-orcid":false,"given":"Miki","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Murofushi","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoko","family":"Komura","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6756-3260","authenticated-orcid":false,"given":"Katsuya","family":"Ohbuchi","sequence":"additional","affiliation":[{"name":"Tsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshikazu","family":"Higami","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0049-0084","authenticated-orcid":false,"given":"Hideaki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhito","family":"Uezono","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Supportive and Palliative Care Research Support Office, National Cancer Center Hospital East, Chiba 277-8577, Japan"},{"name":"Department of Comprehensive Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1113\/jphysiol.1906.sp001148","article-title":"On some physiological actions of ergot","volume":"34","author":"Dale","year":"1906","journal-title":"J. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/cphy.c160007","article-title":"Dendritic release of neurotransmitters","volume":"7","author":"Ludwig","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1124\/pr.120.019398","article-title":"Is oxytocin \u201cNature\u2019s medicine\u201d?","volume":"72","author":"Carter","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"653","DOI":"10.38212\/2224-6614.3381","article-title":"Identification of oxytocin receptor activating chemical components from traditional Japanese medicines","volume":"29","author":"Maejima","year":"2021","journal-title":"J. Food Drug Anal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114218","DOI":"10.1016\/j.jep.2021.114218","article-title":"Kamikihito, a traditional Japanese Kampo medicine, increases the secretion of oxytocin in rats with acute stress","volume":"276","author":"Tsukada","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/0306-4530(94)90021-3","article-title":"The role of central oxytocin in obsessive compulsive disorder and related normal behavior","volume":"19","author":"Leckman","year":"1994","journal-title":"Psychoneuroendocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7491","DOI":"10.1523\/JNEUROSCI.21-19-07491.2001","article-title":"Cns distribution of members of the two-pore-domain (KCNK) potassium channel family","volume":"21","author":"Talley","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00232-021-00189-8","article-title":"Two-pore domain potassium channel in neurological disorders","volume":"254","author":"Aggarwal","year":"2021","journal-title":"J. Membr. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00424-007-0250-2","article-title":"Up- and down-regulation of the mechano-gated K(2P) channel TREK-1 by PIP (2) and other membrane phospholipids","volume":"455","author":"Chemin","year":"2007","journal-title":"Pflugers Arch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S1063-5823(06)59007-6","article-title":"Regulation of the mechano-gated K2P channel TREK-1 by membrane phospholipids","volume":"59","author":"Chemin","year":"2007","journal-title":"Curr. Top. Membr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"26691","DOI":"10.1074\/jbc.274.38.26691","article-title":"Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel","volume":"274","author":"Maingret","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E1154","DOI":"10.1152\/ajpendo.00223.2004","article-title":"TREK-1 K+ channels couple angiotensin II receptors to membrane depolarization and aldosterone secretion in bovine adrenal glomerulosa cells. Am","volume":"287","author":"Enyeart","year":"2004","journal-title":"J. Physiol. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.bbrc.2008.04.001","article-title":"Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells","volume":"370","author":"Enyeart","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1515\/hsz-2022-0266","article-title":"Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation","volume":"404","author":"Schroeter","year":"2023","journal-title":"Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nature22988","article-title":"K2P2.1 (TREK-1)\u2013activator complexes reveal a cryptic selectivity filter binding site","volume":"547","author":"Lolicato","year":"2017","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-030920-111536","article-title":"Two-pore domain potassium channels as drug targets: Anesthesia and beyond","volume":"61","author":"Mathie","year":"2021","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3389\/fphar.2019.00379","article-title":"Role of TREK-1 in health and disease, focus on the central nervous system","volume":"10","author":"Djillani","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1113\/jphysiol.2002.032094","article-title":"Background and tandem-pore potassium channels in magnocellular neurosecretory cells of the rat supraoptic nucleus","volume":"546","author":"Han","year":"2003","journal-title":"J. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jtcme.2020.04.005","article-title":"Effect of 158 herbal remedies on human TRPV1 and the two-pore domain potassium channels KCNK2, 3 and 9","volume":"10","author":"Herbrechter","year":"2020","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/cns.13450","article-title":"Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice","volume":"27","author":"Wu","year":"2021","journal-title":"CNS Neurosci. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.pharmthera.2018.10.003","article-title":"Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin","volume":"194","author":"Djillani","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.cell.2007.08.024","article-title":"From exotic spice to modern drug?","volume":"130","author":"Singh","year":"2007","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jtcme.2021.08.001","article-title":"Kamikihito rescued depressive-like behaviors and hippocampus neurogenesis in chronic restraint stress rats","volume":"12","author":"Adachi","year":"2022","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.2174\/138161212803216924","article-title":"A review of traditional Japanese medicines and their potential mechanism of action","volume":"18","author":"Uezono","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"146555","DOI":"10.1016\/j.gene.2022.146555","article-title":"KAMPOmics: A framework for multidisciplinary and comprehensive research on Japanese traditional medicine","volume":"831","author":"Yamamoto","year":"2022","journal-title":"Gene"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1177\/1087057104268749","article-title":"A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells","volume":"9","author":"Weaver","year":"2004","journal-title":"J. Biomol. Screen."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4907\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:37:17Z","timestamp":1760107037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":26,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094907"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094907","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}