{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:23:01Z","timestamp":1790623381095,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T00:00:00Z","timestamp":1517875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24300145"],"award-info":[{"award-number":["24300145"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16H05124"],"award-info":[{"award-number":["16H05124"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The contribution of HCN4 pacemaker channels in the autonomic regulation of the sino\u2010atrial node (SAN) has been a matter of debate.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The transgenic overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability, while the conditional knockdown of HCN4 gave rise to sinus arrhythmia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The response of the SAN to \u03b2\u2010adrenergic stimulation was not affected by overexpression or knockdown of HCN4 channels.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>When HCN4 channels were knocked down, the parasympathetic response examined by cervical vagus nerve stimulation (CVNS) was enhanced; the CVNS induced complete sinus pause. The overexpression of HCN4 attenuated bradycardia induced by CVNS only during \u03b2\u2010adrenergic stimulation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We concluded that HCN4 pacemaker channels stabilize the spontaneous firing by attenuating the parasympathetic response of the SAN.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The heart rate is dynamically controlled by the sympathetic and parasympathetic nervous systems that regulate the sinoatrial node (SAN). HCN4 pacemaker channels are the well\u2010known causative molecule of congenital sick sinus syndrome. Although HCN4 channels are activated by cAMP, the sympathetic response of the SAN was preserved in patients carrying loss\u2010of\u2010function mutations of the HCN4 gene. In order to clarify the contribution of HCN4 channels in the autonomic regulation of the SAN, we developed novel gain\u2010of\u2010function mutant mice in which the expression level of HCN4 channels could be reversibly changed from zero to \u223c3 times that in wild\u2010type mice, using tetracycline transactivator and the tetracycline responsive element. We recorded telemetric ECGs in freely moving conscious mice and analysed the heart rate variability. We also evaluated the response of the SAN to cervical vagus nerve stimulation (CVNS). The conditional overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability. The HCN4 overexpression also attenuated bradycardia induced by the CVNS only during the \u03b2\u2010adrenergic stimulation. In contrast, the knockdown of HCN4 gave rise to sinus arrhythmia, and enhanced the parasympathetic response; complete sinus pause was induced by the CVNS. <jats:italic>In vitro<\/jats:italic>, we compared the effects of acetylcholine on the spontaneous action potentials of single pacemaker cells, and found that similar phenotypic changes were induced by genetic manipulation of HCN4 expression both in the presence and absence of \u03b2\u2010adrenergic stimulation. Our study suggests that HCN4 channels attenuate the vagal response of the SAN, and thereby stabilize the spontaneous firing of the SAN.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp275303","type":"journal-article","created":{"date-parts":[[2018,1,10]],"date-time":"2018-01-10T13:14:49Z","timestamp":1515590089000},"page":"809-825","source":"Crossref","is-referenced-by-count":34,"title":["HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node"],"prefix":"10.1113","volume":"596","author":[{"given":"Yuko","family":"Kozasa","sequence":"first","affiliation":[{"name":"Department of Physiology Kurume University School of Medicine  67 Asahi\u2010Machi Kurume 830\u20100011 Japan"},{"name":"Department of Anesthesiology Kurume University School of Medicine  67 Asahi\u2010Machi Kurume 830\u20100011 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