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Murviel-lès-Montpellier, France

Christel C.J.,University of Iowa | Cardona N.,University of Iowa | Mesirca P.,French National Center for Scientific Research | Mesirca P.,French Institute of Health and Medical Research | And 9 more authors.
Journal of Physiology | Year: 2012

Dysregulation of L-type Ca2+ currents in sinoatrial nodal (SAN) cells causes cardiac arrhythmia. Both Cav1.2 and Cav1.3 channels mediate sinoatrial L-type currents. Whether these channels exhibit differences in modulation and localization, which could affect their contribution to pacemaking, is unknown. In this study, we characterized voltage-dependent facilitation (VDF) and subcellular localization of Cav1.2 and Cav1.3 channels in mouse SAN cells and determined how these properties of Cav1.3 affect sinoatrial pacemaking in a mathematical model. Whole cell Ba2+ currents were recorded from SAN cells from mice carrying a point mutation that renders Cav1.2 channels relatively insensitive to dihydropyridine antagonists. The Cav1.2-mediated current was isolated in the presence of nimodipine (1 μm), which was subtracted from the total current to yield the Cav1.3 component. With strong depolarizations (+80 mV), Cav1.2 underwent significantly stronger inactivation than Cav1.3. VDF of Cav1.3 was evident during recovery from inactivation at a time when Cav1.2 remained inactivated. By immunofluorescence, Cav1.3 colocalized with ryanodine receptors in sarcomeric structures while Cav1.2 was largely restricted to the delimiting plasma membrane. Cav1.3 VDF enhanced recovery of pacemaker activity after pauses and positively regulated pacemaking during slow heart rate in a numerical model of mouse SAN automaticity, including preferential coupling of Cav1.3 to ryanodine receptor-mediated Ca2+ release. We conclude that strong VDF and colocalization with ryanodine receptors in mouse SAN cells are unique properties that may underlie a specific role for Cav1.3 in opposing abnormal slowing of heart rate. © 2012 The Physiological Society.

Marger L.,French National Center for Scientific Research | Marger L.,French Institute of Health and Medical Research | Marger L.,Universites Of Montpellier 1And 2 | Mesirca P.,French National Center for Scientific Research | And 26 more authors.
Channels | Year: 2011

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 v1.3, Cav3.1 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 Cav3.1 (Cav3.1-/-), Cav1.3 (Cav1.3 -/-), channels or both (Cav1.3-/-/Ca v3.1-/-). 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 Cav3.1 channels impaired AVNCs pacemaker activity by favoring sporadic block of automaticity leading to cellular arrhythmia. Furthermore, Cav3.1 channels were critical for AVNCs to reach high pacemaking rates under isoproterenol. Unexpectedly, Cav1.3 channels were required for spontaneous automaticity, because Cav1.3-/- and Cav1.3-/-/Cav3.1-/- 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 Cav1.3 channels are required for automaticity, Cav3.1 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 β-adrenergic regulation. © 2011 Landes Bioscience.

Marger L.,French National Center for Scientific Research | Marger L.,French Institute of Health and Medical Research | Marger L.,Universites Of Montpellier 1And 2 | Mesirca P.,French National Center for Scientific Research | And 26 more authors.
Channels | Year: 2011

It is well established that pacemaker activity of the sino-atrial node (SA N) initiates the heartbeat. However, the atrioventricular node (AVN) can generate viable pacemaker activity in case of SAN failure, but we have limited knowledge of the ionic bases of AVN automaticity. We characterized pacemaker activity and ionic currents in automatic myocytes of the mouse AVN. Pacemaking of AVN cells (AVNCs) was lower than that of SAN pacemaker cells (SANCs), both in control conditions and upon perfusion of isoproterenol (ISO). Block of I Na by tetrodotoxin (TTX) or of ICa,L by isradipine abolished AVNCs pacemaker activity. TTX-resistant (INar) and TTX-sensitive (INas) Na+ currents were recorded in mouse AVNCs, as well as T-(ICa,T) and L-type (ICa,L) Ca 2+ currents. ICa,L density was lower than in SA NCs (51%). The density of the hyperpolarization-activated current, (If) and that of the fast component of the delayed rectifier current (IKr) were, respectively, lower (52%) and higher (53%) in AVNCs than in SANCs. Pharmacological inhibition of If by 3 μM ZD-7228 reduced pacemaker activity by 16%, suggesting a relevant role for If in AVNCs automaticity. Some AVNCs expressed also moderate densities of the transient outward K+ current (Ito). In contrast, no detectable slow component of the delayed rectifier current (IKs) could be recorded in AVNCs. The lower densities of If and ICa,L, as well as higher expression of IKr in AVNCs than in SANCs may contribute to the intrinsically slower AVNCs pacemaking than that of SANCs. © 2011 Landes Bioscience.

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