Marger, Laurine Mesirca, Pietro Alig, Jacqueline Torrente, Angelo Dubel, Stefan Engeland, Birgit Kanani, Sandra Fontanaud, Pierre Striessnig, Joerg Shin, Hee-Sup Isbrandt, Dirk Ehmke, Heimo Nargeot, Jooel Mangoni, Matteo E. 2024-01-20T17:02:55Z 2024-01-20T17:02:55Z 2022-01-25 2011-05 1933-6950 https://pubs.kist.re.kr/handle/201004/130364 The atrioventricular node controls cardiac impulse conduction and generates pacemaker activity in case of failure of the sino-atrial node. Understanding the mechanisms of atrioventricular automaticity is important for managing human pathologies of heart rate and conduction. However, the physiology of atrioventricular automaticity is still poorly understood. We have investigated the role of three key ion channel-mediated pacemaker mechanisms namely, Ca(v)1.3, Ca(v)3.1 and HCN channels in automaticity of atrioventricular node cells (AVNCs). We studied atrioventricular conduction and pacemaking of AVNCs in wild-type mice and mice lacking Ca(v)3.1 (Ca(v)3.1(-/-)), Ca(v)1.3 (Ca(v)1.3(-/-)), channels or both (Ca(v)1.3(-/-)/Ca(v)3.1(-/-)). The role of HCN channels in the modulation of atrioventricular cells pacemaking was studied by conditional expression of dominant-negative HCN4 channels lacking cAMP sensitivity. Inactivation of Ca(v)3.1 channels impaired AVNCs pacemaker activity by favoring sporadic block of automaticity leading to cellular arrhythmia. Furthermore, Ca(v)3.1 channels were critical for AVNCs to reach high pacemaking rates under isoproterenol. Unexpectedly, Ca(v)1.3 channels were required for spontaneous automaticity, because Ca(v)1.3(-/-) and Ca(v)1.3(-/-)/ Ca(v)3.1(-/-) AVNCs were completely silent under physiological conditions. Abolition of the cAMP sensitivity of HCN channels reduced automaticity under basal conditions, but maximal rates of AVNCs could be restored to that of control mice by isoproterenol. In conclusion, while Ca(v)1.3 channels are required for automaticity, Ca(v)3.1 channels are important for maximal pacing rates of mouse AVNCs. HCN channels are important for basal AVNCs automaticity but do not appear to be determinant for beta-adrenergic regulation. English TAYLOR & FRANCIS INC Functional roles of Ca(v)1.3, Ca(v)3.1 and HCN channels in automaticity of mouse atrioventricular cells Insights into the atrioventricular pacemaker mechanism Article 10.4161/chan.5.3.15266 1 CHANNELS, v.5, no.3, pp.251 - 261 CHANNELS 5 3 251 261 N scie scopus 000295082900012 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article SICK SINUS SYNDROME SINOATRIAL NODE CALCIUM-CHANNEL CONDUCTION BRADYCARDIA EXPRESSION genetically-engineered mice pacemaker activity atrioventricular node congenital heart block sino-atrial node dysfunction ion channels Ca(v)1.3 channels Ca(v)3.1 channels HCN channels electrophysiology conduction heart rate