{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:01:40Z","timestamp":1784901700942,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["2020R1A2C1008893"],"award-info":[{"award-number":["2020R1A2C1008893"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["2022R1C1C1009146"],"award-info":[{"award-number":["2022R1C1C1009146"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We examined the localization of the 5-hydroxytryptamine (5-HT) receptor and its effects on mouse colonic interstitial cells of Cajal (ICCs) using electrophysiological techniques. Treatment with 5-HT increased the pacemaker activity in colonic ICCs with depolarization of membrane potentials in a dose-dependent manner. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers blocked pacemaker activity and 5-HT-induced effects. Moreover, an adenylate cyclase inhibitor inhibited 5-HT-induced effects, and cell-permeable 8-bromo-cAMP increased the pacemaker activity. Various agonists of the 5-HT receptor subtype were working in colonic ICCs, including the 5-HT4 receptor. In small intestinal ICCs, 5-HT depolarized the membrane potentials transiently. Adenylate cyclase inhibitors or HCN blockers did not show any influence on 5-HT-induced effects. Anoctamin-1 (ANO1) or T-type Ca2+ channel blockers inhibited the pacemaker activity of colonic ICCs and blocked 5-HT-induced effects. A tyrosine protein kinase inhibitor inhibited pacemaker activity in colonic ICCs under controlled conditions but did not show any influence on 5-HT-induced effects. Among mitogen-activated protein kinase (MAPK) inhibitors, a p38 MAPK inhibitor inhibited 5-HT-induced effects on colonic ICCs. Thus, 5-HT\u2019s effect on pacemaker activity in small intestinal and colonic ICCs has excitatory but variable patterns. ANO1, T-type Ca2+, and HCN channels are involved in 5-HT-induced effects, and MAPKs are involved in 5-HT effects in colonic ICCs.<\/jats:p>","DOI":"10.3390\/ijms25073997","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T08:42:34Z","timestamp":1712133754000},"page":"3997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["5-Hydroxytryptamine Enhances the Pacemaker Activity of Interstitial Cells of Cajal in Mouse Colon"],"prefix":"10.3390","volume":"25","author":[{"given":"Xingyou","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawan Kumar","family":"Shahi","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Hyung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9684-4651","authenticated-orcid":false,"given":"Chansik","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Yeoul","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nrgastro.2013.105","article-title":"Serotonin signaling in the gut-functions, dysfunctionsand therapeutic targets","volume":"10","author":"Mawe","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1523\/JNEUROSCI.05-03-00617.1985","article-title":"Morphology and serotonergic innervation of physiologically identified cells of the guinea pig\u2019s myenteric plexus","volume":"5","author":"Erde","year":"1985","journal-title":"J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1113\/jphysiol.2008.160416","article-title":"Strain-specific genetics, anatomy and function of enteric neural serotonergic pathways in inbred mice","volume":"587","author":"Neal","year":"2009","journal-title":"J. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0306-4522(85)90059-4","article-title":"Physiological responses of guinea-pig myenteric neurons secondary to the release of endogenous serotonin by tryptamine","volume":"16","author":"Takaki","year":"1985","journal-title":"Neuroscience"},{"key":"ref_5","first-page":"G403","article-title":"Analysis of the role of 5-HT in the enteric nervous system using anti-idiotopic antibodies to 5-HT receptors","volume":"266","author":"Wade","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1046\/j.1365-2982.2003.00393.x","article-title":"Nicotinic transmission at functionally distinct synapses in descending reflex pathways of the rat colon","volume":"15","author":"Bian","year":"2003","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1053\/j.gastro.2008.12.010","article-title":"Localized release of serotonin (5-hydroxytryptamine) by a fecal pellet regulates migrating motor complexes in murine colon","volume":"136","author":"Heredia","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_8","first-page":"93","article-title":"Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors","volume":"288","author":"Jin","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1053\/j.gastro.2019.04.022","article-title":"Effects of serotonin and slow-release 5-hydroxytryptophan on gastrointestinal motility in a mouse of depression","volume":"157","author":"Israelyan","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8998","DOI":"10.1523\/JNEUROSCI.6684-10.2011","article-title":"Essentail roles of enteric neuronal serotonin in gastrointestinal motility and the development\/survival of enteric dopaminergic neurons","volume":"31","author":"Li","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0165-1838(91)90229-V","article-title":"Opioid, 5-HT1A and \u03b12 receptors localized to subsets of guinea-pig myenteric neurons","volume":"32","author":"Galligan","year":"1991","journal-title":"J. Auton. Nerv. Syst."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1084\/jem.115.2.367","article-title":"Studies on the relationship of 5-hydroxytryptamine and the enterochromaffin cell to anaphylactic shock in mice","volume":"115","author":"Gershon","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4733","DOI":"10.1113\/jphysiol.2014.276337","article-title":"Spontaneous transient hyperpolarizations in the rabbit small intestine","volume":"592","author":"Kito","year":"2014","journal-title":"J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1743-3150.2004.00484.x","article-title":"Ion channels interstitial cells of Cajal as targets for neurotransmitter action","volume":"16","author":"Huizinga","year":"2004","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/jcmm.17087","article-title":"Hyperpolarization-activated cyclic nucleotide-gated channels working as pacemaker channels in colonic interstitial cells of Cajal","volume":"26","author":"Choi","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"129","DOI":"10.4196\/kjpp.2011.15.3.129","article-title":"5-Hydroxytryptamine generates tonic inward currents on pacemaker activity of interstitial cells of Cajal from mouse small intestine","volume":"15","author":"Shahi","year":"2011","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1159\/000430990","article-title":"Regulatory roles of endogenous mitogen-activated protein kinases and tyrosine kinases in the pacemaker activity of colonic interstitial cells of Cajal","volume":"96","author":"Shin","year":"2015","journal-title":"Pharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1365-2982.2007.00963.x","article-title":"5-HT receptors on interstitial cells of Cajal, smooth muscle and enteric nerves","volume":"19","author":"Wouters","year":"2007","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00210-014-0976-2","article-title":"Basal cGMP regulates the resting pacemaker potential frequency of cultured mouse colonic interstitial cells of Cajal","volume":"387","author":"Shahi","year":"2014","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/324470a0","article-title":"Characterization of single pacemaker channels in cardiac Sino-atrial node cells","volume":"324","author":"Difrancesco","year":"1986","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1146\/annurev.pa.36.040196.002333","article-title":"Complexity and diversity of mammalian adenylyl cyclases","volume":"36","author":"Sunahara","year":"1996","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_22","first-page":"157","article-title":"International union of pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)","volume":"46","author":"Hoyer","year":"1994","journal-title":"Pharmacol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1139\/cjpp-2018-0115","article-title":"Hyperpolarization-activated cyclic nucleotide-gated channels: Pathophysiological developmental, and pharmacological insights into their function in cellular excitability","volume":"96","author":"Spinelli","year":"2018","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0091-3057(01)00746-8","article-title":"Molecular, pharmacological and functional diversity of 5-HT receptors","volume":"71","author":"Hoyer","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S0014-5793(97)00820-X","article-title":"Molecular and functional characterization of a 5-HT4 receptor cloned from human strium","volume":"412","author":"Bolndel","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1365-2982.2007.01059.x","article-title":"5-HT4 receptor agonists: Similar but not the same","volume":"20","author":"Lefebvre","year":"2008","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1152\/physrev.00037.2013","article-title":"Interstitial cells: Regulators of smooth muscle function","volume":"94","author":"Sanders","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000446990","article-title":"Regulation of the pacemaker activity of colonic interstitial cells of Cajal by protease-activated receptors: Involvement of hyperpolarization-activated cyclic nucleotide channels","volume":"98","author":"Shin","year":"2016","journal-title":"Pharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1113\/jphysiol.2009.176198","article-title":"Expression of anoctamin 1\/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles","volume":"587","author":"Hwang","year":"2009","journal-title":"J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.pbiomolbio.2010.05.007","article-title":"Recent advances in studies of spontaneous activity in smooth muscle: Ubiquitous pacemaker cells","volume":"102","author":"Takaki","year":"2010","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1113\/jphysiol.2002.028977","article-title":"Muscarinic regulation of pacemaker frequency in murine gastric interstitial cells of Cajal","volume":"546","author":"Kim","year":"2003","journal-title":"J. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101","DOI":"10.7150\/ijms.1.101","article-title":"Tyrosine kinase\u2014Role and significance in cancer","volume":"1","author":"Paul","year":"2004","journal-title":"Int. J. Med. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"34224","DOI":"10.1074\/jbc.M506544200","article-title":"A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase","volume":"280","author":"Zong","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1007\/s00424-003-1204-y","article-title":"Tyrosine kinase inhibition differentially regulates heterologously expressed HCN channels","volume":"447","author":"Yu","year":"2004","journal-title":"Pflug. Arch."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s004240050430","article-title":"Tyrosine kinase inhibition reduces if in rabbit sinoatrial node myocytes","volume":"434","author":"Wu","year":"1997","journal-title":"Pflug. Arch."},{"key":"ref_36","first-page":"153","article-title":"Mitogen-activated protein (MAP) kinase pathways: Reglation and physiological functions","volume":"22","author":"Pearson","year":"2001","journal-title":"Endocr. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7995","DOI":"10.1523\/JNEUROSCI.2069-06.2006","article-title":"Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase","volume":"26","author":"Poolos","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.1523\/JNEUROSCI.4376-06.2007","article-title":"HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2","volume":"27","author":"Fogle","year":"2007","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3997\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:23:01Z","timestamp":1760106181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,3]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25073997"],"URL":"https:\/\/doi.org\/10.3390\/ijms25073997","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,3]]}}}