{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:08:24Z","timestamp":1790755704929,"version":"4.1.0"},"reference-count":27,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["FK 128809"],"award-info":[{"award-number":["FK 128809"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["K 116940"],"award-info":[{"award-number":["K 116940"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["K 132623"],"award-info":[{"award-number":["K 132623"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Research, Development and Innovation Fund of Hungary","award":["TKP2020-NKA-04"],"award-info":[{"award-number":["TKP2020-NKA-04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca2+ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca2+ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca2+ concentration, suggesting an inhibition of Ca2+ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca2+ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca2+-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca2+ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site.<\/jats:p>","DOI":"10.3390\/ijms23031465","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:00:56Z","timestamp":1643320856000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A Central Role for TRPM4 in Ca2+-Signal Amplification and Vasoconstriction"],"prefix":"10.3390","volume":"23","author":[{"given":"Tam\u00e1s","family":"Cs\u00edp\u0151","sequence":"first","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Doctoral School of K\u00e1lm\u00e1n Laki, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gnes","family":"Czikora","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor \u00c1.","family":"F\u00fcl\u00f6p","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Doctoral School of K\u00e1lm\u00e1n Laki, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajnalka","family":"Guly\u00e1s","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Doctoral School of Pharmaceutical Sciences, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibolya","family":"Rutkai","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enik\u0151 P\u00e1sztorn\u00e9","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00f3bert","family":"P\u00f3rsz\u00e1sz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Szalai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kata","family":"B\u00f6lcskei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"Szent\u00e1gothai Research Centre, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Helyes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"Szent\u00e1gothai Research Centre, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-632X","authenticated-orcid":false,"given":"Erika","family":"Pint\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"Szent\u00e1gothai Research Centre, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-1542","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Papp","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Ungv\u00e1ri","sequence":"additional","affiliation":[{"name":"Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"International Training Program in Geroscience, Department of Public Health, Semmelweis University, 1089 Budapest, Hungary"},{"name":"The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, 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