{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:44:08Z","timestamp":1789343048377,"version":"build-2803163510"},"reference-count":53,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004343","name":"Stavros Niarchos Foundation","doi-asserted-by":"publisher","award":["310030_184783"],"award-info":[{"award-number":["310030_184783"]}],"id":[{"id":"10.13039\/501100004343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    TRPM4 is a calcium\u2010activated, voltage\u2010modulated, nonselective ion channel widely expressed in various cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linked\n                    <jats:italic>TRPM4<\/jats:italic>\n                    mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4's functional significance in cardiac physiology, its exact roles in the heart have remained unclear. In this study, we investigated the role of TRPM4 in cardiac physiology in a newly generated\n                    <jats:italic>Trpm4<\/jats:italic>\n                    knockdown mouse model. Male and female\n                    <jats:italic>Trpm4<\/jats:italic>\n                    knockdown (\n                    <jats:italic>Trpm4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) and wild\u2010type mice of different ages (5\u2010 to 12\u2010 week\u2010old (young) and 24\u2010week\u2010old or more (adult)) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, ex vivo ECGs in isolated heart, endocardial mappings, Western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild\u2010type and\n                    <jats:italic>Trpm4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    young (5\u2010 to 12\u2010week\u2010old) mice of either sex. Above 24\u2009weeks of age, adult male\n                    <jats:italic>Trpm4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice showed reduced heart rate and increased heart rate variability. Echocardiography revealed that only adult male\n                    <jats:italic>Trpm4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice exhibited slight left ventricular hypertrophic alterations compared to controls, illustrated by alterations of the mitral valve pressure halftime, the mitral valve E\/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in adult male\n                    <jats:italic>Trpm4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Endocardial mapping recordings showed that applying 5\u2009\u03bcM of the new TRPM4 inhibitor NBA triggered a third\u2010degree atrioventricular block on 40% of wild\u2010type hearts. These results confirm the key role of TRPM4 in the proper structure and electrical function of the heart. It also reveals differences between male and female animals that have never been reported. In addition, the investigation of the effects of NBA on heart function confirms the role of TRPM4 in atrioventricular conduction.\n                  <\/jats:p>","DOI":"10.14814\/phy2.15783","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T06:01:49Z","timestamp":1692684109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Knockdown of the\n                    <scp>TRPM4<\/scp>\n                    channel alters cardiac electrophysiology and hemodynamics in a sex\u2010 and age\u2010dependent manner in mice"],"prefix":"10.14814","volume":"11","author":[{"given":"Prakash","family":"Arullampalam","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Essers","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mey","family":"Boukenna","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Guichard","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8710-0260","authenticated-orcid":false,"given":"Jean\u2010S\u00e9bastien","family":"Rougier","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugues","family":"Abriel","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,21]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2012.06.021"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.712354"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13077"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)89505-2"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/294752a0"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.023"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115256"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179499"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2020.103495"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1988.sp017242"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.117.005680"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00294.2015"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12985"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.116959"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.063974"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00004.2010"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000237864.65019.a5"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12582"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.10.069"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.08.014"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-017-0152-8"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-015-0501-x"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070512"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2006.09.006"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38292"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00719-5"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054131"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.109.930867"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302835"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41348"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.14754"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-020-00831-x"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00360-014-0830-3"},{"key":"e_1_2_12_35_1","first-page":"v","article-title":"Mammalian transient receptor potential (TRP) cation channels. Preface","volume":"223","author":"Nilius B.","year":"2014","journal-title":"Handbook of experimental pharmacology"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M305127200"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411089200"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-003-1221-x"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14220"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073401"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13020258"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(88)90167-1"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00802"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.89.7.745"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2021.643287"},{"key":"e_1_2_12_46_1","first-page":"3","article-title":"Nonselective cation channels","volume":"66","author":"Siemen D.","year":"1993","journal-title":"EXS"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70765-w"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.01.019"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21599"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2010.51.2.151"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac354"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2019.100664"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00478.2003"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.121.009427"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.15783","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T04:43:20Z","timestamp":1703911400000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.15783"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8]]},"references-count":53,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.14814\/phy2.15783"],"URL":"https:\/\/doi.org\/10.14814\/phy2.15783","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.10.26.513825","asserted-by":"object"}]},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8]]},"assertion":[{"value":"2023-06-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e15783"}}