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.
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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. / Marger, Laurine; Mesirca, Pietro; Alig, Jacqueline; Torrente, Angelo; Dubel, Stefan; Engeland, Birgit; Kanani, Sandra; Fontanaud, Pierre; Striessnig, Jörg; Shin, Hee-Sup; Isbrandt, Dirk; Ehmke, Heimo; Nargeot, Joël; Mangoni, Matteo E.
in: CHANNELS, Jahrgang 5, Nr. 3, 3, 2011, S. 251-261.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - 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.
AU - Marger, Laurine
AU - Mesirca, Pietro
AU - Alig, Jacqueline
AU - Torrente, Angelo
AU - Dubel, Stefan
AU - Engeland, Birgit
AU - Kanani, Sandra
AU - Fontanaud, Pierre
AU - Striessnig, Jörg
AU - Shin, Hee-Sup
AU - Isbrandt, Dirk
AU - Ehmke, Heimo
AU - Nargeot, Joël
AU - Mangoni, Matteo E
PY - 2011
Y1 - 2011
N2 - 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 ?-adrenergic regulation.
AB - 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 ?-adrenergic regulation.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Mice, Knockout
KW - Biological Clocks/drug effects/physiology
KW - Adrenergic beta-Agonists/pharmacology
KW - Arrhythmia, Sinus/genetics/metabolism
KW - Atrioventricular Node/cytology/metabolism
KW - Calcium Channels, L-Type/genetics/metabolism
KW - Calcium Channels, T-Type/genetics/metabolism
KW - Cyclic AMP/genetics/metabolism
KW - Cyclic Nucleotide-Gated Cation Channels/genetics/metabolism
KW - Isoproterenol/pharmacology
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Mice, Knockout
KW - Biological Clocks/drug effects/physiology
KW - Adrenergic beta-Agonists/pharmacology
KW - Arrhythmia, Sinus/genetics/metabolism
KW - Atrioventricular Node/cytology/metabolism
KW - Calcium Channels, L-Type/genetics/metabolism
KW - Calcium Channels, T-Type/genetics/metabolism
KW - Cyclic AMP/genetics/metabolism
KW - Cyclic Nucleotide-Gated Cation Channels/genetics/metabolism
KW - Isoproterenol/pharmacology
U2 - 10.4161/chan.5.3.15266
DO - 10.4161/chan.5.3.15266
M3 - SCORING: Journal article
VL - 5
SP - 251
EP - 261
JO - CHANNELS
JF - CHANNELS
SN - 1933-6950
IS - 3
M1 - 3
ER -
