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Pietro Mesirca - One of the best experts on this subject based on the ideXlab platform.
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Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart Automaticity
Scientific Reports, 2020Co-Authors: M Baudot, L Fossier, L Talssi, Isabelle Bidaud, Joel Nargeot, Eleonora Torre, Julien Louradour, Angelo Torrente, Stéphanie Barrère-lemaire, Pietro MesircaAbstract:Cardiac Automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2+ channels (SAN-VGCCs). The role of SAN-VGCCs in Automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Cav1.3 (Cav1.3-/-) or Cav3.1 (Cav3.1-/-) channels and double mutant Cav1.3-/-/Cav3.1-/- mice expressing only Cav1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN Automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na+ channels. In beating SAN cells, ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca2+ clock" mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart Automaticity and define an integral role for these channels in mechanisms that control the heartbeat.
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channelopathies of voltage gated l type cav1 3 α1d and t type cav3 1 α1g ca2 channels in dysfunction of heart Automaticity
Pflügers Archiv: European Journal of Physiology, 2020Co-Authors: Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Matteo E MangoniAbstract:The heart Automaticity is a fundamental physiological function in vertebrates. The cardiac impulse is generated in the sinus node by a specialized population of spontaneously active myocytes known as "pacemaker cells." Failure in generating or conducting spontaneous activity induces dysfunction in cardiac Automaticity. Several families of ion channels are involved in the generation and regulation of the heart Automaticity. Among those, voltage-gated L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels play important roles in the spontaneous activity of pacemaker cells. Ca2+ channel channelopathies specifically affecting cardiac Automaticity are considered rare. Recent research on familial disease has identified mutations in the Cav1.3-encoding CACNA1D gene that underlie congenital sinus node dysfunction and deafness (OMIM # 614896). In addition, both Cav1.3 and Cav3.1 channels have been identified as pathophysiological targets of sinus node dysfunction and heart block, caused by congenital autoimmune disease of the cardiac conduction system. The discovery of channelopathies linked to Cav1.3 and Cav3.1 channels underscores the importance of Ca2+ channels in the generation and regulation of heart's Automaticity.
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heart Automaticity in mice lacking l type cav1 3 and t type cav3 1 ca2 channels insights into the cardiac pacemaker mechanism
Archives of Cardiovascular Diseases Supplements, 2018Co-Authors: M Baudot, L Fossier, L Talssi, Heesup Shin, Joerg Striessnig, Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Joel Nargeot, Stephanie BarrerelemaireAbstract:Introduction Sino-atrial node (SAN) pacemaker activity is generated by ion channels of the plasma membrane, such as hyperpolarization-activated “funny” f-(HCN), Ca2+ channels and ryanodine receptor (RyR) – dependent Ca2+ release from the sarcoplasmic reticulum (SR). It is currently disputed whether Ca2+ release from RyRs could sustain viable pacemaker activity provided preserved SR Ca2+ content. While working myocytes express L-type Cav1.2 channels to maintain SR Ca2+ content, SAN cells express also L-type Cav1.3 and T-type Cav3.1 channels to generate pacemaking. Objectives We used mutant mice carrying concomitant ablation of Cav1.3 and Cav3.1 (Cav1.3−/−/Cav3.1−/−) to study the importance of these channels in Automaticity. We also investigated the role of f-HCN channels and RyR-dependent Ca2+ release in residual pacemaker activity of mutant mice. Methods We employed in vivo telemetric recordings of heart rate (HR) in Cav1.3−/−, Cav3.1−/− and Cav1.3−/−/Cav3.1−/− mice. We studied the consequences of pharmacologic inhibition of f-HCN and TTX-sensitive Na+ channels in mutant mice using Langendorff perfused hearts or optical mapping (OM) of the pacemaker impulse in intact SAN preparations (SANs). Results Cav ablation reduced HR in mice: Cav3.1−/− (−7.6%, n = 11), Cav1.3−/− (−24.4%, n = 8), Cav1.3−/−/Cav3.1−/− (−35%, n = 11). In OM experiments on SANs, concomitant inhibition of f-HCN and Nav1.1 channels slowed pacemaking in wild-type (−48%, n = 7) and Cav3.1−/− (−37%, n = 7), while arresting Automaticity in 4/6 of Cav1.3−/−, 3/6 of Cav1.3−/−/Cav3.1−/−. When present, residual pacemaking was reduced by 82%. Similar results were obtained using isolated Cav1.3−/−/Cav3.1−/− pacemaker cells were Automaticity arrested in 5/9 cells tested, or was reduced by 80% in 4/9 cells. Conclusion Heart Automaticity is primarily generated by Cav1.3 and f-HCN channels. RyR-dependent Ca2+ release cannot sustain Automaticity following concomitant targeting of Cav1.3 and f-HCN channels.
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role of l type cav1 3 ca2 channels in ca2 handling and san pacemaker activity altered by external conditions
Archives of Cardiovascular Diseases Supplements, 2017Co-Authors: Angelo G. Torrente, M Baudot, Pietro Mesirca, B Isabelle, B Christian, R Julien, S JoergAbstract:Introduction Membrane currents and Ca2+ handling generate Sinoatrial node (SAN) Automaticity. Several studies showed the negative effect of membrane current impairment, while it is unknown how abnormal Ca2+ affect pacemaking. Purpose To investigate SAN Automaticity when Ca2+ handling is altered by external conditions. Methods We video recorded contraction amplitude and spontaneous rate of SAN cells. Results In WT, 0.9 mM external Ca2+ ([Ca2+]0) reduces cell shortening, while 3 mM increased it, compared to control solution (1.8 mM [Ca2+]0). Lowering [Ca2+]0 to 0.9 mM did not affect WT Automaticity, while high [Ca2+]0 dysregulate it without changing the average rate. L-type channels (LTCCs) are the main Ca2+ source in SAN cells, with Cav1.3 as the dominant isoform and Cav1.2 less expressed. To discern their role during abnormal [Ca2+]0, we used mice lacking Cav1.3 channels (Cav1.3−/−). As in WT, 0.9 mM [Ca2+]0 decreased cell shortening in Cav1.3−/−, while only a tendency to increase was determined by 3 mM [Ca2+]0. Also, high [Ca2+]0 significantly reduced spontaneous rate in Cav1.3−/− cells. Stimulation of WT cells with the LTCC dihydropyridine agonist BayK 8644 (BayK) increased cell shortening and spontaneous rate. Under BayK, Cav1.3−/− cells showed similar increase of contraction amplitude but reduced rate acceleration than WT. We repeated this protocol with a mouse where Cav1.2 is dihydropyridines insensitive (Cav1.2DHP−/−). Cav1.2DHP−/− SAN cells responded like WT to abnormal [Ca2+]0. Instead, BayK caused rate increase equivalent to WT but reduced contraction shortening in Cav1.2DHP−/−. Conclusion Abnormal increase of Ca2+ influx dysregulates Automaticity in WT cells, likely through hyper-stimulation of Ca2+ activated currents. Moreover, selective stimulation of Cav1.2 and/or Cav1.3 with BayK suggests that Cav1.2 maintain the bulk of Ca2+ allowing proper contraction, while Cav1.3 mainly carry the influx of Ca2+ needed to trigger SAN Automaticity.
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The Ion Channel-Kinase, TRPM7, is Required for Cardiac Automaticity
Biophysical Journal, 2013Co-Authors: Rajan Sah, Matteo E Mangoni, Pietro Mesirca, Xenos Mason, Marjolein Van Den Boogert, Christopher Bates-withers, Jonathan N. Rosen, John D. Mably, David E. ClaphamAbstract:Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a calcium-permeant channel-kinase highly expressed in heart, is required for cardiac Automaticity, sinoatrial node (SAN) and atrioventricular node (AVN) function. We find larger TRPM7 currents in myocardial cells exhibiting Automaticity such as embryonic ventricular myocytes (EVM) and SAN cells, as compared to quiescent adult ventricular myocytes. TRPM7 disruption in cultured EVM reduces spontaneous Ca2+ transient firing rates, impairing Automaticity in vitro. Likewise, morpholino mediated TRPM7 knock-down in zebrafish embryo slows heart rate in vivo. Cardiac-targeted TRPM7 deletion in mouse (KO) eliminates TRPM7 current in SAN, inducing episodes of sinus pauses, AVN block and cardiomyopathy. Freshly isolated SAN from KO mice exhibit diminished Ca2+ transient firing rates and a blunted diastolic Ca2+ rise. Moreover, action potential firing rates are diminished in KO SAN due to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, If, are diminished in both SAN and AVN from KO mice. We conclude that TRPM7 both regulates Hcn4 expression and provides a novel, previously unrecognized diastolic Ca2+ current at hyperpolarized membrane potentials, each contributing to diastolic membrane depolarization and myocardial Automaticity in SAN and AVN.
Matteo E Mangoni - One of the best experts on this subject based on the ideXlab platform.
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channelopathies of voltage gated l type cav1 3 α1d and t type cav3 1 α1g ca2 channels in dysfunction of heart Automaticity
Pflügers Archiv: European Journal of Physiology, 2020Co-Authors: Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Matteo E MangoniAbstract:The heart Automaticity is a fundamental physiological function in vertebrates. The cardiac impulse is generated in the sinus node by a specialized population of spontaneously active myocytes known as "pacemaker cells." Failure in generating or conducting spontaneous activity induces dysfunction in cardiac Automaticity. Several families of ion channels are involved in the generation and regulation of the heart Automaticity. Among those, voltage-gated L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels play important roles in the spontaneous activity of pacemaker cells. Ca2+ channel channelopathies specifically affecting cardiac Automaticity are considered rare. Recent research on familial disease has identified mutations in the Cav1.3-encoding CACNA1D gene that underlie congenital sinus node dysfunction and deafness (OMIM # 614896). In addition, both Cav1.3 and Cav3.1 channels have been identified as pathophysiological targets of sinus node dysfunction and heart block, caused by congenital autoimmune disease of the cardiac conduction system. The discovery of channelopathies linked to Cav1.3 and Cav3.1 channels underscores the importance of Ca2+ channels in the generation and regulation of heart's Automaticity.
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The Ion Channel-Kinase, TRPM7, is Required for Cardiac Automaticity
Biophysical Journal, 2013Co-Authors: Rajan Sah, Matteo E Mangoni, Pietro Mesirca, Xenos Mason, Marjolein Van Den Boogert, Christopher Bates-withers, Jonathan N. Rosen, John D. Mably, David E. ClaphamAbstract:Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a calcium-permeant channel-kinase highly expressed in heart, is required for cardiac Automaticity, sinoatrial node (SAN) and atrioventricular node (AVN) function. We find larger TRPM7 currents in myocardial cells exhibiting Automaticity such as embryonic ventricular myocytes (EVM) and SAN cells, as compared to quiescent adult ventricular myocytes. TRPM7 disruption in cultured EVM reduces spontaneous Ca2+ transient firing rates, impairing Automaticity in vitro. Likewise, morpholino mediated TRPM7 knock-down in zebrafish embryo slows heart rate in vivo. Cardiac-targeted TRPM7 deletion in mouse (KO) eliminates TRPM7 current in SAN, inducing episodes of sinus pauses, AVN block and cardiomyopathy. Freshly isolated SAN from KO mice exhibit diminished Ca2+ transient firing rates and a blunted diastolic Ca2+ rise. Moreover, action potential firing rates are diminished in KO SAN due to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, If, are diminished in both SAN and AVN from KO mice. We conclude that TRPM7 both regulates Hcn4 expression and provides a novel, previously unrecognized diastolic Ca2+ current at hyperpolarized membrane potentials, each contributing to diastolic membrane depolarization and myocardial Automaticity in SAN and AVN.
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genesis and regulation of the heart Automaticity
Physical Review, 2008Co-Authors: Matteo E Mangoni, Joel NargeotAbstract:The heart Automaticity is a fundamental physiological function in higher organisms. The spontaneous activity is initiated by specialized populations of cardiac cells generating periodical electrica...
Angelo G. Torrente - One of the best experts on this subject based on the ideXlab platform.
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channelopathies of voltage gated l type cav1 3 α1d and t type cav3 1 α1g ca2 channels in dysfunction of heart Automaticity
Pflügers Archiv: European Journal of Physiology, 2020Co-Authors: Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Matteo E MangoniAbstract:The heart Automaticity is a fundamental physiological function in vertebrates. The cardiac impulse is generated in the sinus node by a specialized population of spontaneously active myocytes known as "pacemaker cells." Failure in generating or conducting spontaneous activity induces dysfunction in cardiac Automaticity. Several families of ion channels are involved in the generation and regulation of the heart Automaticity. Among those, voltage-gated L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels play important roles in the spontaneous activity of pacemaker cells. Ca2+ channel channelopathies specifically affecting cardiac Automaticity are considered rare. Recent research on familial disease has identified mutations in the Cav1.3-encoding CACNA1D gene that underlie congenital sinus node dysfunction and deafness (OMIM # 614896). In addition, both Cav1.3 and Cav3.1 channels have been identified as pathophysiological targets of sinus node dysfunction and heart block, caused by congenital autoimmune disease of the cardiac conduction system. The discovery of channelopathies linked to Cav1.3 and Cav3.1 channels underscores the importance of Ca2+ channels in the generation and regulation of heart's Automaticity.
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heart Automaticity in mice lacking l type cav1 3 and t type cav3 1 ca2 channels insights into the cardiac pacemaker mechanism
Archives of Cardiovascular Diseases Supplements, 2018Co-Authors: M Baudot, L Fossier, L Talssi, Heesup Shin, Joerg Striessnig, Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Joel Nargeot, Stephanie BarrerelemaireAbstract:Introduction Sino-atrial node (SAN) pacemaker activity is generated by ion channels of the plasma membrane, such as hyperpolarization-activated “funny” f-(HCN), Ca2+ channels and ryanodine receptor (RyR) – dependent Ca2+ release from the sarcoplasmic reticulum (SR). It is currently disputed whether Ca2+ release from RyRs could sustain viable pacemaker activity provided preserved SR Ca2+ content. While working myocytes express L-type Cav1.2 channels to maintain SR Ca2+ content, SAN cells express also L-type Cav1.3 and T-type Cav3.1 channels to generate pacemaking. Objectives We used mutant mice carrying concomitant ablation of Cav1.3 and Cav3.1 (Cav1.3−/−/Cav3.1−/−) to study the importance of these channels in Automaticity. We also investigated the role of f-HCN channels and RyR-dependent Ca2+ release in residual pacemaker activity of mutant mice. Methods We employed in vivo telemetric recordings of heart rate (HR) in Cav1.3−/−, Cav3.1−/− and Cav1.3−/−/Cav3.1−/− mice. We studied the consequences of pharmacologic inhibition of f-HCN and TTX-sensitive Na+ channels in mutant mice using Langendorff perfused hearts or optical mapping (OM) of the pacemaker impulse in intact SAN preparations (SANs). Results Cav ablation reduced HR in mice: Cav3.1−/− (−7.6%, n = 11), Cav1.3−/− (−24.4%, n = 8), Cav1.3−/−/Cav3.1−/− (−35%, n = 11). In OM experiments on SANs, concomitant inhibition of f-HCN and Nav1.1 channels slowed pacemaking in wild-type (−48%, n = 7) and Cav3.1−/− (−37%, n = 7), while arresting Automaticity in 4/6 of Cav1.3−/−, 3/6 of Cav1.3−/−/Cav3.1−/−. When present, residual pacemaking was reduced by 82%. Similar results were obtained using isolated Cav1.3−/−/Cav3.1−/− pacemaker cells were Automaticity arrested in 5/9 cells tested, or was reduced by 80% in 4/9 cells. Conclusion Heart Automaticity is primarily generated by Cav1.3 and f-HCN channels. RyR-dependent Ca2+ release cannot sustain Automaticity following concomitant targeting of Cav1.3 and f-HCN channels.
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role of l type cav1 3 ca2 channels in ca2 handling and san pacemaker activity altered by external conditions
Archives of Cardiovascular Diseases Supplements, 2017Co-Authors: Angelo G. Torrente, M Baudot, Pietro Mesirca, B Isabelle, B Christian, R Julien, S JoergAbstract:Introduction Membrane currents and Ca2+ handling generate Sinoatrial node (SAN) Automaticity. Several studies showed the negative effect of membrane current impairment, while it is unknown how abnormal Ca2+ affect pacemaking. Purpose To investigate SAN Automaticity when Ca2+ handling is altered by external conditions. Methods We video recorded contraction amplitude and spontaneous rate of SAN cells. Results In WT, 0.9 mM external Ca2+ ([Ca2+]0) reduces cell shortening, while 3 mM increased it, compared to control solution (1.8 mM [Ca2+]0). Lowering [Ca2+]0 to 0.9 mM did not affect WT Automaticity, while high [Ca2+]0 dysregulate it without changing the average rate. L-type channels (LTCCs) are the main Ca2+ source in SAN cells, with Cav1.3 as the dominant isoform and Cav1.2 less expressed. To discern their role during abnormal [Ca2+]0, we used mice lacking Cav1.3 channels (Cav1.3−/−). As in WT, 0.9 mM [Ca2+]0 decreased cell shortening in Cav1.3−/−, while only a tendency to increase was determined by 3 mM [Ca2+]0. Also, high [Ca2+]0 significantly reduced spontaneous rate in Cav1.3−/− cells. Stimulation of WT cells with the LTCC dihydropyridine agonist BayK 8644 (BayK) increased cell shortening and spontaneous rate. Under BayK, Cav1.3−/− cells showed similar increase of contraction amplitude but reduced rate acceleration than WT. We repeated this protocol with a mouse where Cav1.2 is dihydropyridines insensitive (Cav1.2DHP−/−). Cav1.2DHP−/− SAN cells responded like WT to abnormal [Ca2+]0. Instead, BayK caused rate increase equivalent to WT but reduced contraction shortening in Cav1.2DHP−/−. Conclusion Abnormal increase of Ca2+ influx dysregulates Automaticity in WT cells, likely through hyper-stimulation of Ca2+ activated currents. Moreover, selective stimulation of Cav1.2 and/or Cav1.3 with BayK suggests that Cav1.2 maintain the bulk of Ca2+ allowing proper contraction, while Cav1.3 mainly carry the influx of Ca2+ needed to trigger SAN Automaticity.
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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
Channels, 2011Co-Authors: Laurine Marger, Joerg Striessnig, Angelo G. Torrente, Pietro Mesirca, Jacqueline Alig, Stefan J Dubel, Birgit Engeland, Sandra Kanani, Pierre Fontanaud, Heesup ShinAbstract: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 β-adrenergic regulation.
Isabelle Bidaud - One of the best experts on this subject based on the ideXlab platform.
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Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart Automaticity
Scientific Reports, 2020Co-Authors: M Baudot, L Fossier, L Talssi, Isabelle Bidaud, Joel Nargeot, Eleonora Torre, Julien Louradour, Angelo Torrente, Stéphanie Barrère-lemaire, Pietro MesircaAbstract:Cardiac Automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2+ channels (SAN-VGCCs). The role of SAN-VGCCs in Automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Cav1.3 (Cav1.3-/-) or Cav3.1 (Cav3.1-/-) channels and double mutant Cav1.3-/-/Cav3.1-/- mice expressing only Cav1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN Automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na+ channels. In beating SAN cells, ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca2+ clock" mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart Automaticity and define an integral role for these channels in mechanisms that control the heartbeat.
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channelopathies of voltage gated l type cav1 3 α1d and t type cav3 1 α1g ca2 channels in dysfunction of heart Automaticity
Pflügers Archiv: European Journal of Physiology, 2020Co-Authors: Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Matteo E MangoniAbstract:The heart Automaticity is a fundamental physiological function in vertebrates. The cardiac impulse is generated in the sinus node by a specialized population of spontaneously active myocytes known as "pacemaker cells." Failure in generating or conducting spontaneous activity induces dysfunction in cardiac Automaticity. Several families of ion channels are involved in the generation and regulation of the heart Automaticity. Among those, voltage-gated L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels play important roles in the spontaneous activity of pacemaker cells. Ca2+ channel channelopathies specifically affecting cardiac Automaticity are considered rare. Recent research on familial disease has identified mutations in the Cav1.3-encoding CACNA1D gene that underlie congenital sinus node dysfunction and deafness (OMIM # 614896). In addition, both Cav1.3 and Cav3.1 channels have been identified as pathophysiological targets of sinus node dysfunction and heart block, caused by congenital autoimmune disease of the cardiac conduction system. The discovery of channelopathies linked to Cav1.3 and Cav3.1 channels underscores the importance of Ca2+ channels in the generation and regulation of heart's Automaticity.
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heart Automaticity in mice lacking l type cav1 3 and t type cav3 1 ca2 channels insights into the cardiac pacemaker mechanism
Archives of Cardiovascular Diseases Supplements, 2018Co-Authors: M Baudot, L Fossier, L Talssi, Heesup Shin, Joerg Striessnig, Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Joel Nargeot, Stephanie BarrerelemaireAbstract:Introduction Sino-atrial node (SAN) pacemaker activity is generated by ion channels of the plasma membrane, such as hyperpolarization-activated “funny” f-(HCN), Ca2+ channels and ryanodine receptor (RyR) – dependent Ca2+ release from the sarcoplasmic reticulum (SR). It is currently disputed whether Ca2+ release from RyRs could sustain viable pacemaker activity provided preserved SR Ca2+ content. While working myocytes express L-type Cav1.2 channels to maintain SR Ca2+ content, SAN cells express also L-type Cav1.3 and T-type Cav3.1 channels to generate pacemaking. Objectives We used mutant mice carrying concomitant ablation of Cav1.3 and Cav3.1 (Cav1.3−/−/Cav3.1−/−) to study the importance of these channels in Automaticity. We also investigated the role of f-HCN channels and RyR-dependent Ca2+ release in residual pacemaker activity of mutant mice. Methods We employed in vivo telemetric recordings of heart rate (HR) in Cav1.3−/−, Cav3.1−/− and Cav1.3−/−/Cav3.1−/− mice. We studied the consequences of pharmacologic inhibition of f-HCN and TTX-sensitive Na+ channels in mutant mice using Langendorff perfused hearts or optical mapping (OM) of the pacemaker impulse in intact SAN preparations (SANs). Results Cav ablation reduced HR in mice: Cav3.1−/− (−7.6%, n = 11), Cav1.3−/− (−24.4%, n = 8), Cav1.3−/−/Cav3.1−/− (−35%, n = 11). In OM experiments on SANs, concomitant inhibition of f-HCN and Nav1.1 channels slowed pacemaking in wild-type (−48%, n = 7) and Cav3.1−/− (−37%, n = 7), while arresting Automaticity in 4/6 of Cav1.3−/−, 3/6 of Cav1.3−/−/Cav3.1−/−. When present, residual pacemaking was reduced by 82%. Similar results were obtained using isolated Cav1.3−/−/Cav3.1−/− pacemaker cells were Automaticity arrested in 5/9 cells tested, or was reduced by 80% in 4/9 cells. Conclusion Heart Automaticity is primarily generated by Cav1.3 and f-HCN channels. RyR-dependent Ca2+ release cannot sustain Automaticity following concomitant targeting of Cav1.3 and f-HCN channels.
Joel Nargeot - One of the best experts on this subject based on the ideXlab platform.
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Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart Automaticity
Scientific Reports, 2020Co-Authors: M Baudot, L Fossier, L Talssi, Isabelle Bidaud, Joel Nargeot, Eleonora Torre, Julien Louradour, Angelo Torrente, Stéphanie Barrère-lemaire, Pietro MesircaAbstract:Cardiac Automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2+ channels (SAN-VGCCs). The role of SAN-VGCCs in Automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Cav1.3 (Cav1.3-/-) or Cav3.1 (Cav3.1-/-) channels and double mutant Cav1.3-/-/Cav3.1-/- mice expressing only Cav1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN Automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na+ channels. In beating SAN cells, ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca2+ clock" mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart Automaticity and define an integral role for these channels in mechanisms that control the heartbeat.
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heart Automaticity in mice lacking l type cav1 3 and t type cav3 1 ca2 channels insights into the cardiac pacemaker mechanism
Archives of Cardiovascular Diseases Supplements, 2018Co-Authors: M Baudot, L Fossier, L Talssi, Heesup Shin, Joerg Striessnig, Angelo G. Torrente, Isabelle Bidaud, Pietro Mesirca, Joel Nargeot, Stephanie BarrerelemaireAbstract:Introduction Sino-atrial node (SAN) pacemaker activity is generated by ion channels of the plasma membrane, such as hyperpolarization-activated “funny” f-(HCN), Ca2+ channels and ryanodine receptor (RyR) – dependent Ca2+ release from the sarcoplasmic reticulum (SR). It is currently disputed whether Ca2+ release from RyRs could sustain viable pacemaker activity provided preserved SR Ca2+ content. While working myocytes express L-type Cav1.2 channels to maintain SR Ca2+ content, SAN cells express also L-type Cav1.3 and T-type Cav3.1 channels to generate pacemaking. Objectives We used mutant mice carrying concomitant ablation of Cav1.3 and Cav3.1 (Cav1.3−/−/Cav3.1−/−) to study the importance of these channels in Automaticity. We also investigated the role of f-HCN channels and RyR-dependent Ca2+ release in residual pacemaker activity of mutant mice. Methods We employed in vivo telemetric recordings of heart rate (HR) in Cav1.3−/−, Cav3.1−/− and Cav1.3−/−/Cav3.1−/− mice. We studied the consequences of pharmacologic inhibition of f-HCN and TTX-sensitive Na+ channels in mutant mice using Langendorff perfused hearts or optical mapping (OM) of the pacemaker impulse in intact SAN preparations (SANs). Results Cav ablation reduced HR in mice: Cav3.1−/− (−7.6%, n = 11), Cav1.3−/− (−24.4%, n = 8), Cav1.3−/−/Cav3.1−/− (−35%, n = 11). In OM experiments on SANs, concomitant inhibition of f-HCN and Nav1.1 channels slowed pacemaking in wild-type (−48%, n = 7) and Cav3.1−/− (−37%, n = 7), while arresting Automaticity in 4/6 of Cav1.3−/−, 3/6 of Cav1.3−/−/Cav3.1−/−. When present, residual pacemaking was reduced by 82%. Similar results were obtained using isolated Cav1.3−/−/Cav3.1−/− pacemaker cells were Automaticity arrested in 5/9 cells tested, or was reduced by 80% in 4/9 cells. Conclusion Heart Automaticity is primarily generated by Cav1.3 and f-HCN channels. RyR-dependent Ca2+ release cannot sustain Automaticity following concomitant targeting of Cav1.3 and f-HCN channels.
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genesis and regulation of the heart Automaticity
Physical Review, 2008Co-Authors: Matteo E Mangoni, Joel NargeotAbstract:The heart Automaticity is a fundamental physiological function in higher organisms. The spontaneous activity is initiated by specialized populations of cardiac cells generating periodical electrica...
