Novel physiological role of HCN4 channel in the sinoatrial node revealed with TET-off genetic switch system

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05124
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Kurume University
• Principal Investigator: TAKANO Makoto 久留米大学, 医学部, 教授 (30236252)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ペースメーカーチャネル / 洞房結節 / 自律神経

Outline of Final Research Achievements

The heart rate is dynamically controlled by the autonomic nervous systems that regulate the sinoatrial node (SAN). HCN4 pacemaker channels are well-known molecular marker of SAN, although its physiological role still remains matter of debate. We therefore developed novel transgenic mice in which expression level of HCN4 channels could be reversibly changed from zero to ~3 times of that in wild type mice, using tetracycline trans-activator and tetracycline responsive element. We found that overexpression of HCN4 channels reduced the parasympathetic response of SAN, whereas genetic silencing of HCN4 channels generated opposite phenotypic changes. Our study suggested that HCN4 channels attenuate the vagal response of SAN, and prevent excessive bradycardia. We concluded that HCN4 channels maintain the heart rate variability within a physiological range by this mechanism.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

心臓は一生涯にわたって拍動し続ける。これはわずか数万個のペースメーカー細胞という特殊な細胞が繰り返し電気的な興奮を発生するためである。この細胞の機能が低下すると、身体活動に支障をきたすほど脈拍数が低下することがある。我々は、ペースメーカー細胞にだけ存在するHCN4というイオンチャネル（細胞膜上に存在し、電気の通り道となる特殊な蛋白質）が、過度の脈拍数低下を防ぐ機能を持つことを明らかにした。