{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:25:26Z","timestamp":1781108726348,"version":"3.54.1"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2020-118694RB-I00"],"award-info":[{"award-number":["PID2020-118694RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["P2022\/BMD-7229"],"award-info":[{"award-number":["P2022\/BMD-7229"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,12,5]]},"abstract":"<jats:p>\n                    In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide\u2013gated type 4 (HCN4) channel, which contributes to the pacemaker current (I\n                    <jats:sub>f<\/jats:sub>\n                    ) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (I\n                    <jats:sub>HCN4<\/jats:sub>\n                    ) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and\/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. I\n                    <jats:sub>HCN4<\/jats:sub>\n                    generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases I\n                    <jats:sub>f<\/jats:sub>\n                    and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2305135120","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T13:37:18Z","timestamp":1701351438000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6124-2236","authenticated-orcid":false,"given":"Anabel","family":"C\u00e1mara-Checa","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1041-930X","authenticated-orcid":false,"given":"Francesca","family":"Perin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Virgen de las Nieves University Hospital, Granada 18014, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada, Granada 18014, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Rubio-Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Dago","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3635-1446","authenticated-orcid":false,"given":"Teresa","family":"Crespo-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-8818","authenticated-orcid":false,"given":"Josu","family":"Rap\u00fan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Mar\u00edn","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Cebri\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5522-195X","authenticated-orcid":false,"given":"Ricardo","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7979-7758","authenticated-orcid":false,"given":"Juan","family":"Tamargo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6424-9687","authenticated-orcid":false,"given":"Ricardo","family":"Caballero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Gregorio Mara\u00f1\u00f3n, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, 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